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Journal articles on the topic "53BP1"
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Thukral, S. K., G. C. Blain, K. K. Chang, and S. Fields. "Distinct residues of human p53 implicated in binding to DNA, simian virus 40 large T antigen, 53BP1, and 53BP2." Molecular and Cellular Biology 14, no. 12 (December 1994): 8315–21. http://dx.doi.org/10.1128/mcb.14.12.8315-8321.1994.
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We identified a minimal domain of human p53 required for the transactivation of a p53 response element in Saccharomyces cerevisiae. This domain contains the central region of p53 sufficient for specific DNA binding, which colocalizes with the region responsible for binding simian virus 40 large T antigen, 53BP1, and 53BP2. Thirty amino acid positions, including natural mutational hot spots (R175, R213, R248, R249, and R273), in the minimal DNA-binding domain were mutated by alanine substitution. Alanine substitutions at positions R213, R248, R249, D281, R282, R283, E286, and N288 affected transactivation but allowed binding to at least one of the three interacting proteins; these amino acids may be involved in amino acid-base pair contacts. Surprisingly, alanine substitution at the mutational hot spot R175 did not affect DNA binding, transactivation, or T-antigen binding, although it nearly eliminated binding to 53BP1 and 53BP2. Mutation of H168 significantly affected only T-antigen binding, and mutation of E285 affected only 53BP1 binding. Thus, we implicate specific residues of p53 in different DNA and protein interactions.
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Thukral, S. K., G. C. Blain, K. K. Chang, and S. Fields. "Distinct residues of human p53 implicated in binding to DNA, simian virus 40 large T antigen, 53BP1, and 53BP2." Molecular and Cellular Biology 14, no. 12 (December 1994): 8315–21. http://dx.doi.org/10.1128/mcb.14.12.8315.
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We identified a minimal domain of human p53 required for the transactivation of a p53 response element in Saccharomyces cerevisiae. This domain contains the central region of p53 sufficient for specific DNA binding, which colocalizes with the region responsible for binding simian virus 40 large T antigen, 53BP1, and 53BP2. Thirty amino acid positions, including natural mutational hot spots (R175, R213, R248, R249, and R273), in the minimal DNA-binding domain were mutated by alanine substitution. Alanine substitutions at positions R213, R248, R249, D281, R282, R283, E286, and N288 affected transactivation but allowed binding to at least one of the three interacting proteins; these amino acids may be involved in amino acid-base pair contacts. Surprisingly, alanine substitution at the mutational hot spot R175 did not affect DNA binding, transactivation, or T-antigen binding, although it nearly eliminated binding to 53BP1 and 53BP2. Mutation of H168 significantly affected only T-antigen binding, and mutation of E285 affected only 53BP1 binding. Thus, we implicate specific residues of p53 in different DNA and protein interactions.
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Du Toit, Andrea. "Limiting 53BP1." Nature Reviews Molecular Cell Biology 14, no. 3 (February 13, 2013): 132. http://dx.doi.org/10.1038/nrm3532.
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Jullien, Denis, Paola Vagnarelli, William C. Earnshaw, and Yasuhisa Adachi. "Kinetochore localisation of the DNA damage response component 53BP1 during mitosis." Journal of Cell Science 115, no. 1 (January 1, 2002): 71–79. http://dx.doi.org/10.1242/jcs.115.1.71.
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53BP1 is a vertebrate BRCT motif protein, originally described as a direct interactor of p53, which has recently been shown to be implicated in the early response to DNA damage. Upon DNA damage, 53BP1 re-localises to discrete nuclear foci that are thought to represent sites of DNA lesions and becomes hyperphosphorylated. Several observations suggest that 53BP1 is a direct substrate for the ataxia telangiectasia mutated (ATM) kinase. So far, 53BP1 behaviour during mitosis has not been reported in detail. We have examined 53BP1 subcellular distribution in mitotic cells using several antibodies against 53BP1, and ectopic expression of GFP-tagged 53BP1. We found that 53BP1 significantly colocalised with CENP-E to kinetochores. 53BP1 is loaded to kinetochores in prophase, before CENP-E, and is released by mid-anaphase. By expressing various GFP-tagged 53BP1 truncations, the kinetochore binding domain has been mapped to a 380 residue portion of the protein that excludes the nuclear localisation signal and the BRCT motifs. Like many kinetochore-associated proteins involved in mitotic checkpoint signalling, more 53BP1 appears to accumulate on the kinetochores of chromosomes not aligned on the metaphase plate. Finally, we show that 53BP1 is hyperphosphorylated in mitotic cells, and undergoes an even higher level of phosphorylation in response to spindle disruption with colcemid. Our data suggest that 53BP1 may have a role in checkpoint signalling during mitosis and provide the evidence that DNA damage response machinery and mitotic checkpoint may share common molecular components.
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Ward, Irene M., Simone Difilippantonio, Kay Minn, Melissa D. Mueller, Julian R. Molina, Xiaochun Yu, Craig S. Frisk, Thomas Ried, Andre Nussenzweig, and Junjie Chen. "53BP1 Cooperates with p53 and Functions as a Haploinsufficient Tumor Suppressor in Mice." Molecular and Cellular Biology 25, no. 22 (November 15, 2005): 10079–86. http://dx.doi.org/10.1128/mcb.25.22.10079-10086.2005.
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ABSTRACT p53 binding protein 1 (53BP1) is a putative DNA damage sensor that accumulates at sites of double-strand breaks (DSBs) in a manner dependent on histone H2AX. Here we show that the loss of one or both copies of 53BP1 greatly accelerates lymphomagenesis in a p53-null background, suggesting that 53BP1 and p53 cooperate in tumor suppression. A subset of 53BP1−/− p53−/− lymphomas, like those in H2AX−/− p53−/− mice, were diploid and harbored clonal translocations involving antigen receptor loci, indicating misrepair of DSBs during V(D)J recombination as one cause of oncogenic transformation. Loss of a single 53BP1 allele compromised genomic stability and DSB repair, which could explain the susceptibility of 53BP1+/− mice to tumorigenesis. In addition to structural aberrations, there were high rates of chromosomal missegregation and accumulation of aneuploid cells in 53BP1−/− p53+/+ and 53BP1−/− p53−/− tumors as well as in primary 53BP1−/− splenocytes. We conclude that 53BP1 functions as a dosage-dependent caretaker that promotes genomic stability by a mechanism that preserves chromosome structure and number.
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Wang, Dejie, Jian Ma, Maria Victoria Botuyan, Gaofeng Cui, Yuqian Yan, Donglin Ding, Yingke Zhou, et al. "ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication." Science Advances 7, no. 25 (June 2021): eabd9208. http://dx.doi.org/10.1126/sciadv.abd9208.
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53BP1 activates nonhomologous end joining (NHEJ) and inhibits homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Dissociation of 53BP1 from DSBs and consequent activation of HR, a less error-prone pathway than NHEJ, helps maintain genome integrity during DNA replication; however, the underlying mechanisms are not fully understood. Here, we demonstrate that E3 ubiquitin ligase SPOP promotes HR during S phase of the cell cycle by excluding 53BP1 from DSBs. In response to DNA damage, ATM kinase–catalyzed phosphorylation of SPOP causes a conformational change in SPOP, revealed by x-ray crystal structures, that stabilizes its interaction with 53BP1. 53BP1-bound SPOP induces polyubiquitination of 53BP1, eliciting 53BP1 extraction from chromatin by a valosin-containing protein/p97 segregase complex. Our work shows that SPOP facilitates HR repair over NHEJ during DNA replication by contributing to 53BP1 removal from chromatin. Cancer-derived SPOP mutations block SPOP interaction with 53BP1, inducing HR defects and chromosomal instability.
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Ward, Irene M., Bernardo Reina-San-Martin, Alexandru Olaru, Kay Minn, Koji Tamada, Julie S. Lau, Marilia Cascalho, et al. "53BP1 is required for class switch recombination." Journal of Cell Biology 165, no. 4 (May 24, 2004): 459–64. http://dx.doi.org/10.1083/jcb.200403021.
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53BP1 participates early in the DNA damage response and is involved in cell cycle checkpoint control. Moreover, the phenotype of mice and cells deficient in 53BP1 suggests a defect in DNA repair (Ward et al., 2003b). Therefore, we asked whether or not 53BP1 would be required for the efficient repair of DNA double strand breaks. Our data indicate that homologous recombination by gene conversion does not depend on 53BP1. Moreover, 53BP1-deficient mice support normal V(D)J recombination, indicating that 53BP1 is not required for “classic” nonhomologous end joining. However, class switch recombination is severely impaired in the absence of 53BP1, suggesting that 53BP1 facilitates DNA end joining in a way that is not required or redundant for the efficient closing of RAG-induced strand breaks. These findings are similar to those observed in mice or cells deficient in the tumor suppressors ATM and H2AX, further suggesting that the functions of ATM, H2AX, and 53BP1 are closely linked.
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Rappold, Irene, Kuniyoshi Iwabuchi, Takayasu Date, and Junjie Chen. "Tumor Suppressor P53 Binding Protein 1 (53bp1) Is Involved in DNA Damage–Signaling Pathways." Journal of Cell Biology 153, no. 3 (April 30, 2001): 613–20. http://dx.doi.org/10.1083/jcb.153.3.613.
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The tumor suppressor p53 binding protein 1 (53BP1) binds to the DNA-binding domain of p53 and enhances p53-mediated transcriptional activation. 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage–signaling pathways. Thus, we investigated the potential role of 53BP1 in DNA damage–signaling pathways. Here, we report that 53BP1 becomes hyperphosphorylated and forms discrete nuclear foci in response to DNA damage. These foci colocalize at all time points with phosphorylated H2AX (γ-H2AX), which has been previously demonstrated to localize at sites of DNA strand breaks. 53BP1 foci formation is not restricted to γ-radiation but is also detected in response to UV radiation as well as hydroxyurea, camptothecin, etoposide, and methylmethanesulfonate treatment. Several observations suggest that 53BP1 is regulated by ataxia telangiectasia mutated (ATM) after DNA damage. First, ATM-deficient cells show no 53BP1 hyperphosphorylation and reduced 53BP1 foci formation in response to γ-radiation compared with cells expressing wild-type ATM. Second, wortmannin treatment strongly inhibits γ-radiation–induced hyperphosphorylation and foci formation of 53BP1. Third, 53BP1 is readily phosphorylated by ATM in vitro. Taken together, these results suggest that 53BP1 is an ATM substrate that is involved early in the DNA damage–signaling pathways in mammalian cells.
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Salvador Moreno, Naike, Jing Liu, Karen M. Haas, Laurie L. Parker, Chaitali Chakraborty, Stephen J. Kron, Kurt Hodges, et al. "The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair." Nucleic Acids Research 47, no. 6 (February 28, 2019): 2703–15. http://dx.doi.org/10.1093/nar/gkz138.
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Abstract P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.
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Tripathi, Vivek, Tirunelvely Nagarjuna, and Sagar Sengupta. "BLM helicase–dependent and –independent roles of 53BP1 during replication stress–mediated homologous recombination." Journal of Cell Biology 178, no. 1 (June 25, 2007): 9–14. http://dx.doi.org/10.1083/jcb.200610051.
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Mutations in BLM helicase cause Bloom syndrome, characterized by predisposition to all forms of cancer. We demonstrate that BLM, signal transducer 53BP1, and RAD51 interact during stalled replication. Interactions between the three proteins have functional consequences. Lack of 53BP1 decreases the cell survival and enhanced chromosomal aberration after replication arrest. 53BP1 exhibits both BLM-dependent and -independent anti-recombinogenic functions in human and mouse cells. Both BLM and 53BP1 abrogate endogenous RAD51 foci formation and disrupt RAD51 polymerization. Consequently, loss of BLM and 53BP1 synergistically enhances stress-dependent homologous recombination. These results provide evidence regarding the cooperation between BLM and 53BP1 during maintenance of genomic integrity.
Dissertations / Theses on the topic "53BP1"
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Mason, Helen. "Investigating the role of 53BP1 in regulating gene transcription." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3207/.
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53BP1 is a DNA damage responsive protein that plays a crucial role in checkpoint activation and DNA repair. In addition to its involvement in the cellular response to DNA damage, it has been suggested that 53BP1 can also function to regulate gene expression. 53BP1 was originally identified in a yeast two-hybrid screen for novel modulators of p53 transcriptional activity. Despite this, the role of 53BP1 in transcriptional regulation remains poorly understood. To investigate the effect of 53BP1 on cellular transcription, a microarray approach was utilised to study the gene expression patterns in cells treated with and without 53BP1 siRNA, before and after ionising radiation. Microarray analysis identified numerous genes whose expression was regulated by 53BP1 in the absence and presence of DNA damage. These data suggest that 53BP1 functions as a transcriptional regulator. In support of this, in vitro and in vivo studies have shown that 53BP1 binds to the transcriptional co-activators, CBP and p300. These findings indicate that the binding of 53BP1 to CBP and p300 may be facilitating its role as a regulator of transcription.
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Chang, Kai-wei. "The identification of proteins interacting with the 53BP1 tandem Tudor domains." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=32548.
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Tumor protein p53 binding protein 1 (53BP1) is a cell cycle checkpoint protein that is important in the early DNA double strand break (DSB) response signal pathway. Aberrant reduction or lack of 53BP1 is found in significant proportions of carcinomas. 53BP1 is recruited to DSB sites and forms foci through its tandem Tudor domain by recognizing dimethylated lysines in histones. The 53BP1 tandem Tudor (53BP1TT) domain consists of two tightly packed Tudor domains follow by a C-terminal alpha helix, and actively binds to methylated histone lysines H4K20 and H3K79. I hypothesized that 53BP1TT domain can potentially interact with non-histone targets, which contain methylated residues, and may be involved in the maintenance of genomic stability. The primary goal of the work presented in this thesis is to identify the proteins that interact with the 53BP1TT domain. I performed a proteomic screen by employing in vitro transcription/translation coupled reactions on pools of cDNA plasmids and identified two putative 53BP1TT targets, brahma-related gene 1 (BRG1), which is a chromatin remodeling catalytic subunit that has helicase and ATPase activities, and is thought to regulate transcription by altering the chromatin structure, and checkpoint kinase 1 (CHK1), which mediates DNA damage signal to downstream damage responsive proteins and initiates cell cycle checkpoint arrest. I demonstrated that both endogenous BRG1 and CHK1 interacted with the 53BP1TT domain in glutathione-S-transferase pulldown assays. Co-immunoprecipitation between ectopically expressed BRG1 and 53BP1 was observed. Interestingly, the interaction between endogenous BRG1 and 53BP1 was observed only after DNA damaLa protéine 53BP1 (p53 binding protein 1) (53BP1) est une protéine impliquée dans la surveillance du cycle cellulaire (checkpoint) activé par les brisures d'ADN double-brin (double-strand break ou DSB). L'absence ou la réduction d'expression de 53BP1 est une caractéristique retrouvée dans la majorité de carcinomes. 53BP1 est recrutée rapidement aux sites de DSB par ses domaines Tudor tandem qui reconnaissent les résidus de lysines dimethylées des histones. Les domaines 53BP1 Tudor tandem (53BP1TT) est comprennent deux domaines Tudor suivi par une hélice alpha au C-terminal et ces domaines ont une affinité spécifique pour les lysines methylées H4K20 et H3K79 des histones. Étant donné que les domaines Tudor tandem sont généralement caractérisés par leur interaction avec le des résidus methylés, j'ai émis l'hypothèse que les 53BP1TT pourraient d'interagir avec des protéines autres que les histones contenant des résidus methylés, ce qui révèlerait un rôle important dans le maintien de la stabilité génomique. Donc, le principal objectif du travail présenté dans cette thèse est l'identification de protéines interagissant avec 53BP1TT. Pour ce faire, j'ai employé la réaction couplée de transcription et traduction in vitro sur une banque d'ADNc. Ceci m'a permis d'identifier deux cibles putatives de 53BP1TT, soit CHK1 (checkpoint kinase 1) et BRG1 (brahma-related gene 1). Chk1 est connu de jouer un rôle clé dans la cascade de signalisation des brisures d'ADN double-brin et pour son interaction avec les homologues de levure de 53BP1, tandis que BRG1 est la sous-unité ATPase des complexes SWI/SNF impliques dans le remodelage de la chroma
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Leriche, Mélissa. "Mise en évidence d’une interaction entre la protéine 53BP1 et les fragments d’Okazaki." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS065.
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Le maintien de l’intégrité du génome est un processus crucial à la vie cellulaire. Ce n’est que récemment que les protéines de liaison à l’ARN (« RNA-binding protein » ou RBP) ont été montré être impliquées dans ce processus. En présence d’ADN endommagé, les RBP régulent l’expression des gènes de réponse aux dommages de l’ADN et contrôlent le destin cellulaire. Elles jouent également un rôle plus direct dans la prévention et la réparation des dommages de l’ADN. De plus, des ARN sont présents aux sites de dommages de l’ADN et participent au maintien de l’intégrité du génome. Ainsi, le laboratoire recherche des acteurs protéiques capables de lier directement l’ARN au sein des protéines médiatrices de la réponse aux dommages de l’ADN. Un des candidats est la protéine 53BP1 (p53 binding protein 1) qui contient un domaine de liaison à l’ARN nommé domaine GAR (« Glycine-Arginine Rich »). 53BP1 est un acteur central de la signalisation des cassures double-brin de l’ADN et de la régulation de leur réparation par le processus de jonction d’extrémités non homologues pendant la phase G1 du cycle cellulaire. Le recrutement de 53BP1 aux sites de dommages de l'ADN dépend à la fois d'interactions directes entre 53BP1 et des marques d’histones, mais aussi d’une composante ARN.L’objectif était d’étudier l’interaction entre 53BP1 et l’ARN.Grâce aux méthodes de CLIP (« CrossLinking and ImmunoPrecipitation ») et de 2C (« Complex Capture »), nous avons montré que 53BP1 possède une activité de liaison directe à l'ARN, via son domaine GAR. Nous avons identifié l’acide nucléique interagissant avec 53BP1 comme étant une chimère ARN-ADN constituée d’une partie d’environ 10 ribonucléotides, suivie d’environ 100 désoxyribonucléotides. Ce type de molécule est très similaire à celle des fragments d’Okazaki qui sont impliqués dans l’initiation de la synthèse du brin retardé de la fourche de réplication. Par la méthode de SIRF (« In Situ Protein Interaction with Nascent DNA Replication Forks »), nous avons montré que 53BP1 est présent au niveau de l’ADN naissant, dans un contexte de réplication normal. De plus, la déplétion de la sous-unité catalytique de la primase (PRIM1) qui synthétise l’amorce ARN des fragments d’Okazaki, conduit à la diminution de la présence de 53BP1 à proximité d’ADN naissant. La déplétion de PRIM1 affecte également l’interaction de 53BP1 avec la chimère ARN-ADN in vivo. Ces résultats indiquent que 53BP1 est présent à la fourche de réplication via une interaction directe avec les fragments d’Okazaki. Enfin, sous stress réplicatif induit par l’hydroxyurée, la présence de 53BP1 au niveau de l’ADN naissant est fortement augmentée, indiquant que 53BP1 s’accumule aux fourches de réplication bloquées. L'ensemble de ces résultats montre que 53BP1 est une protéine de liaison aux ARN qui interagit directement avec les fragments d’OkazakiMaintenance of genome integrity is essential for cell survival. It is only recently that RNA-binding proteins (RBPs) have been shown as fundamental actors in this process. In the presence of DNA damage, RBPs regulate the expression of DNA damage response (DDR) related genes and control cell fate. RBPs also have a more direct role in preventing and repairing DNA damage. Moreover, some RNAs are present at sites of DNA damage and, thus, participate in the maintenance of genome integrity. The laboratory is interested in proteins that are both able to directly bind RNA and involved in DDR. One candidate is the 53BP1 protein (p53 binding protein 1) that contains an RNA-binding domain called GAR domain (Glycin-Arginin Rich). 53BP1 is a key protein mediating the signalling of DNA double-strand breaks and channels DNA repair to the non-homologous end-joining pathway during the G1 phase of the cell cycle. The recruitment of 53BP1 to sites of DNA damage depends on both histones marks and an RNA component.The objective was to study the interaction between 53BP1 and RNA.By using CLIP (CrossLinking and Immunoprecipitation) and 2C (Complex Capture) technologies, we showed that 53BP1 presents a direct RNA-binding activity within its GAR domain. We identified the nucleic acid interacting with 53BP1 as being an RNA-DNA chimera composed of about 10 ribonucleotides, followed by about 100 dexoribonucleotides. This type of entity is highly similar to that of Okazaki fragments, that are involved in the initiation of lagging strand synthesis at replication forks. By using the SIRF method (In Situ Protein Interaction with Nascent DNA Replication Forks), we showed that 53BP1 is localized at sites of newly synthetized DNA, under normal conditions of replication. Furthermore, depletion of the catalytic sub-unit of the primase (PRIM1), that catalyzes the synthesis of the RNA primer of Okazaki fragments, results in a decrease in 53BP1 at sites of newly synthetized DNA. PRIM1 depletion also decreases the interaction between 53BP1 and RNA-DNA chimera in vivo. These results indicate that 53BP1 is localized at the replication fork through a direct interaction with Okazaki fragments. Likewise, under replicative stress induced by hydroxyurea, the presence of 53BP1 at the newly synthetized DNA is increased, indicating that 53BP1 accumulates at stalled replication forks. Altogether, these results show that 53BP1 is an RNA-binding protein that directly interacts with Okazaki fragments
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Oliveira, Sara Raquel da Silva. "Polimorfismos nos genes TP53, 53BP1 e ATM: Susceptibilidade para cancro do colo do útero." Master's thesis, Faculdade de Medicina da Universidade do Porto, 2007. http://hdl.handle.net/10216/7616.
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Mestrado em Medicina e Oncologia MolecularMaster Degree Course in Molecular and Oncology Medicine
O ciclo celular de uma célula prossegue, normalmente, sem que hajam interrupções. Contudo, quando ocorrem danos no DNA, nomeadamente quebras da dupla hélice, as células têm a capacidade de parar transientemente a sua proliferação. Como resposta a esta ameaça, as células eucarióticas desenvolveram mecanismos que detectam a presença deste DNA danificado, permitindo assim, que na maioria das situações, este seja reparado. Esta resposta é mobilizada pela acção de uma proteína cinase, a pATM. Após serem identificadas as zonas de DNA danificado, a pATM é então activada, indo fosforilar uma série de proteínas envolvidas no ciclo celular. Uma destas proteínas é a p53, a qual tem sido associada ao desenvolvimento de praticamente todos os tipos de neoplasias humanas. Outra proteína fundamental na resposta celular a quebras de dupla hélice do DNA é a p53BP1. Porém, o modo de actuação desta proteína no ciclo celular não foi ainda bem definido. No presente trabalho realizou-se um estudo retrospectivo com um total de 700 amostras de raspagens cervico-vaginais provenientes de mulheres da região Norte de Portugal, com o intuito de se avaliar a influência dos polimorfismos genéticos nos genes TP53, 53BP1 e ATM, na susceptibilidade para cancro do colo do útero. Actualmente, sabe-se que para o desenvolvimento desta neoplasia, a infecção pelo Vírus do Papiloma Humano é um requisito necessário embora, não suficiente. Quanto ao polimorfismo R72P na p53 não foram encontradas evidências de susceptibilidade aumentada quer para o desenvolvimento de lesões do colo do útero quer de carcinoma invasivo associado ao genótipo Arg/Arg (p>0.05). Relativamente ao polimorfismo C1236G no gene 53BP1, verificou-se pela primeira vez que a infecção por HPV16 aumenta o risco de progressão para HSIL em portadores do alelo C, contrariamente aos portadores do genótipo GG (p=0.00002; OR=5.6 e p=0.299 respectivamente). Observou-se ainda uma influência do polimorfismo G5557A no gene ATM na idade para a qual ocorre progressão de lesões de baixo-grau para lesões de alto-grau e carcinoma invasivo. A idade mediana de aparecimento de lesões de alto-grau ou carcinoma invasivo nos portadores do alelo A foi de 43.0 anos comparativamente com os 59.0 anos para os homozigóticos do alelo G (p=0.001).
Cell cycle progresses without interruptions. However, when DNA damage occurs, namely double strand breaks, cells are able to stops transiently her proliferation. In response to this threat, eucariotic cells develop mechanisms, which detect this damage DNA. Thereby generally this DNA can be repaired. The kinase protein, pATM, carries out this response. Upon identification of the damage DNA, pATM is activated and fosforilates a set of proteins involved in cell cycle. One of these proteins is p53, which have been associated with the development of almost all type of human tumours. Other essencial protein in cellular response to double strand breaks is p53BP1. However, the exactly mechanism of this protein in cell cycle remains controversial. We developed a retrospective study considering a total of 700 cervical specimens of women from Northern region of Portugal, in order to evaluate the influence of genetic polymorphisms in TP53, 53BP1 and ATM genes in cervical cancer susceptibility. Actually is known that for the development of this neoplasia, the infection with human papillomavirus is a necessary condition perhaps not sufficient. Regarding the R72P polymorphisms in p53, no statistically significant differences were found. Therefore, at least in our population, the p53 R72P polymorphism is not associated with an increased susceptibility to squamous intraepithelial lesions or cervical cancer development (p>0.05). Analysing the C1236G polymorphism, we verify that the infection of HPV16 increases the risk of progression for high-grade squamous intraepithelial lesions in C carrier patients. Contrary, this effect in patients with GG genotype was not found (p=0.00002; OR=5.6 e p=0.299 respectively). The ATM 5557A allele was found to influence the age at which the progression from low-grade squamous intraepithelial lesions to high-grade squamous intraepithelial lesions or invase carcinoma occurs. The median age of onset cancer in ATM A allele carries was 43.0 years old comparing to 59.0 years old in G allele homozygous (p=0.001).
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Noon, Angela T. "Investigating the role of 53BP1 in DNA double strand break repair and checkpoint signalling." Thesis, University of Sussex, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496789.
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DNA double strand breaks arise endogenously in the cell as a result of routine activities such as metabolism and also as a result of exposure to exogenous agents such as ionising radiation. Repair of DNA DSBs is coordinated by two major repair pathways in mammalian cells; non-homologous end joining and homologous recombination. Nonhomologous end joining is the dominant repair pathway during G1 and G2 phase of the mammalian cell cycle. The core non-homologous end joining factors Ku, DNA-PKcs, XLF, DNA Ligase IV and XRCC4 are essential for efficient and accurate rejoining of double strand breaks. In 2004, Riballo et al. discovered that the ATM protein kinase and the Artemis endonuclease were important for repair of a fraction of DNA double strand breaks in G1 phase cells.
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Oliveira, Sara Raquel da Silva. "Polimorfismos nos genes TP53, 53BP1 e ATM: Susceptibilidade para cancro do colo do útero." Dissertação, Faculdade de Medicina da Universidade do Porto, 2007. http://hdl.handle.net/10216/7616.
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Mestrado em Medicina e Oncologia MolecularMaster Degree Course in Molecular and Oncology Medicine
O ciclo celular de uma célula prossegue, normalmente, sem que hajam interrupções. Contudo, quando ocorrem danos no DNA, nomeadamente quebras da dupla hélice, as células têm a capacidade de parar transientemente a sua proliferação. Como resposta a esta ameaça, as células eucarióticas desenvolveram mecanismos que detectam a presença deste DNA danificado, permitindo assim, que na maioria das situações, este seja reparado. Esta resposta é mobilizada pela acção de uma proteína cinase, a pATM. Após serem identificadas as zonas de DNA danificado, a pATM é então activada, indo fosforilar uma série de proteínas envolvidas no ciclo celular. Uma destas proteínas é a p53, a qual tem sido associada ao desenvolvimento de praticamente todos os tipos de neoplasias humanas. Outra proteína fundamental na resposta celular a quebras de dupla hélice do DNA é a p53BP1. Porém, o modo de actuação desta proteína no ciclo celular não foi ainda bem definido. No presente trabalho realizou-se um estudo retrospectivo com um total de 700 amostras de raspagens cervico-vaginais provenientes de mulheres da região Norte de Portugal, com o intuito de se avaliar a influência dos polimorfismos genéticos nos genes TP53, 53BP1 e ATM, na susceptibilidade para cancro do colo do útero. Actualmente, sabe-se que para o desenvolvimento desta neoplasia, a infecção pelo Vírus do Papiloma Humano é um requisito necessário embora, não suficiente. Quanto ao polimorfismo R72P na p53 não foram encontradas evidências de susceptibilidade aumentada quer para o desenvolvimento de lesões do colo do útero quer de carcinoma invasivo associado ao genótipo Arg/Arg (p>0.05). Relativamente ao polimorfismo C1236G no gene 53BP1, verificou-se pela primeira vez que a infecção por HPV16 aumenta o risco de progressão para HSIL em portadores do alelo C, contrariamente aos portadores do genótipo GG (p=0.00002; OR=5.6 e p=0.299 respectivamente). Observou-se ainda uma influência do polimorfismo G5557A no gene ATM na idade para a qual ocorre progressão de lesões de baixo-grau para lesões de alto-grau e carcinoma invasivo. A idade mediana de aparecimento de lesões de alto-grau ou carcinoma invasivo nos portadores do alelo A foi de 43.0 anos comparativamente com os 59.0 anos para os homozigóticos do alelo G (p=0.001).
Cell cycle progresses without interruptions. However, when DNA damage occurs, namely double strand breaks, cells are able to stops transiently her proliferation. In response to this threat, eucariotic cells develop mechanisms, which detect this damage DNA. Thereby generally this DNA can be repaired. The kinase protein, pATM, carries out this response. Upon identification of the damage DNA, pATM is activated and fosforilates a set of proteins involved in cell cycle. One of these proteins is p53, which have been associated with the development of almost all type of human tumours. Other essencial protein in cellular response to double strand breaks is p53BP1. However, the exactly mechanism of this protein in cell cycle remains controversial. We developed a retrospective study considering a total of 700 cervical specimens of women from Northern region of Portugal, in order to evaluate the influence of genetic polymorphisms in TP53, 53BP1 and ATM genes in cervical cancer susceptibility. Actually is known that for the development of this neoplasia, the infection with human papillomavirus is a necessary condition perhaps not sufficient. Regarding the R72P polymorphisms in p53, no statistically significant differences were found. Therefore, at least in our population, the p53 R72P polymorphism is not associated with an increased susceptibility to squamous intraepithelial lesions or cervical cancer development (p>0.05). Analysing the C1236G polymorphism, we verify that the infection of HPV16 increases the risk of progression for high-grade squamous intraepithelial lesions in C carrier patients. Contrary, this effect in patients with GG genotype was not found (p=0.00002; OR=5.6 e p=0.299 respectively). The ATM 5557A allele was found to influence the age at which the progression from low-grade squamous intraepithelial lesions to high-grade squamous intraepithelial lesions or invase carcinoma occurs. The median age of onset cancer in ATM A allele carries was 43.0 years old comparing to 59.0 years old in G allele homozygous (p=0.001).
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Dibitetto, D. "DYNAMIC BINDING OF RAD9/53BP1 ON DNA LESIONS PROMOTES ACCURATE REPAIR AND GENOME STABILITY." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/466131.
Full textAbstract:
All living organisms are constantly exposed to physical and chemical sources that challenge the integrity of the genome. Considering the high number of chemical and physical insults potentially deleterious to which cells are constantly exposed, the maintenance of genome stability is for all living organisms a main challenge during the cellular life cycle. The ability to cope with DNA damage is crucial for cellular proliferation and, in higher eukaryotes, the loss of function of genes responding to DNA damage often results in genetic syndromes and cancer predisposition. Recognition of DNA damaged structures and their accurate repair are two crucial events that involve several factors and multiple specialized pathways. These events are finely orchestrated by the cell cycle checkpoints aimed to sense DNA damage, arrest cellular proliferation and activate the most accurate repair pathway.
At DNA double strand breaks (DSB, the most cytotoxic lesions), homology-directed repair initiates with the 5’ strand nucleolytic degradation of the broken end, a process called resection. In all the eukaryotes, resection is tightly regulated and, not surprisingly, mutations in resection machinery genes are associated with high genome instability and therefore cancer predisposition. In the past we proposed that the Rad9 checkpoint factor, through the interaction with modified histones physically inhibits the ssDNA accumulation at DSB. Importantly, this function is conserved with the mammalian counterpart 53BP1.
In this thesis, using budding yeast as model system, I have been involved in three projects focusing on the role of Rad9 in DSB repair pathway choice and how the chromatin positioning of this factor is dynamically regulated in response to these lesions.
In a first part, I collaborated in the comprehension of Rad9 genetic and functional interactions with different repair factors during DSB metabolism. In brief, we found that Rad9 positioning around DSB ends are important for tethering of DSB ends, resection start and, most importantly, recruitment of recombination factors. Our findings provided a molecular explanation how Rad9 inhibition facilitates Homologous Recombination (HR), preventing the Non Homologous End Joining repair (NHEJ).
Later, I studied the role of the Slx4-Rtt107 complex in modulating checkpoint signaling and nucleolytic processing during homology-directed repair of DSBs. Using different genetics and biochemical approaches, I described a novel Slx4 function in supporting DSB resection through the inhibition of the formation of a complex between Rad9 and the checkpoint factor Dpb11 (TOPBP1 in mammals). In mammals, biallelic mutations in SLX4 are associated with the Fanconi Anemia, a genetic disorder associated with defects in DNA repair and high cancer risk. Considering this, our results may be important for understanding how Slx4 protects genome stability and favors cellular proliferation in human beings.
In the last part, I have been involved in an international collaboration with Dr. Marcus B. Smolka (Cornell University, Ithaca, NY, USA). Here I studied the role of Dpb11 in coordinating the recruitment of Rad9 during the resection process. We found that a constitutive interaction between Dpb11 and Rad9 severely abrogates ssDNA accumulation in cells responding to DSB lesions, suggesting that this interaction is a crucial point of regulation regarding this process. In human cells, SLX4 shares functional homology with BRCA1, whose interaction with TOPBP1 is mutually exclusive with TOPBP1-53BP1. Our results suggest that TOPBP1, through the coordinated recruitment of pro- and anti-recombination factor, is an essential regulator of DNA repair and genome stability.
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Etourneaud, Laure. "Impact de la lamine B1 sur la stabilité du génome." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS301.
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Un lien étroit existe entre l’intégrité du génome et l’architecture nucléaire. Les lamines, composants majeurs de l’enveloppe nucléaire sont impliquées dans de nombreux processus nucléaires, tels que la réplication, la transcription et le maintien de l’architecture nucléaire. Il a notamment été rapporté que les lamines de type A sont impliquées dans la réparation des cassures double brin de l’ADN et la stabilité des télomères. Toutefois, peu d’études ont été réalisées sur les lamines de type B. Fait intéressant, il a été observé que l’accumulation de la lamine B1 est retrouvée dans différentes tumeurs. Cependant, les conséquences d’une dérégulation de cette lamine sur la stabilité du génome restent peu documentées.Au cours de ma thèse, je me suis intéressée à l’impact d’une dérégulation de la lamine B1 sur le maintien de la stabilité du génome, notamment sur la réparation des cassures double brin de l’ADN et la stabilité des télomères. Nous avons pu mettre en évidence que la surexpression de lamine B1 conduit à un défaut de réparation par NHEJ, associé à une diminution de recrutement de 53BP1 aux dommages radio-induits. Nous avons également démontré que la lamine B1 interagit directement avec 53BP1, protéine impliquée dans le choix de la voie de réparation, et que cette interaction est régulée en cas de dommages à l’ADN. En effet, la liaison entre ces deux protéines est rompue après dommages en condition endogène, ce qui n’est pas le cas après surexpression de la lamine B1. Ce défaut de recrutement de 53BP1 aux dommages pourrait rendre compte de la diminution de l’efficacité du NHEJ. De plus, j’ai pu identifier les domaines protéiques impliqués dans cette interaction. Il est intéressant de noter que la surexpression du domaine de la lamine B1 impliquée dans l’interaction mime la surexpression de la lamine B1 entière. Au contraire, la lamine B1 délétée de ce domaine n’a aucun impact sur le recrutement de 53BP1 et la persistance des dommages. Ces différentes données confortent notre hypothèse quant à la séquestration de 53BP1 après surexpression de lamine B1.En parallèle, nous avons pu démontrer que la surexpression de la lamine B1 entraine l’apparition de diplochromosomes concomitants à une sénescence accrue. Ce phénomène d’endoréplication peut être induit par des défauts télomériques, tels que des télomères dysfonctionnels ou déprotégés. De façon intéressante, mes données montrent que la surexpression de la lamine B1 entrainent des dommages télomériques. Nous avons également établit que la lamine B1 interagit avec TRF2, protéine du complexe « shelterin » permettant la protection des télomères contre la signalisation des dommages à l’ADN. La rétention putative de TRF2 par la lamine B1 pourrait être à l’origine des défauts télomériques observés après la surexpression de cette dernièreCette étude démontre de nouveaux rôles de la lamine B1 dans le maintien de la stabilité du génome, notamment à travers ses interactions avec deux protéines clefs dans la réparation des cassures double brin et la stabilité des télomères. Cela nous ouvre de nouvelles pistes de recherche qui permettront une meilleure compréhension des mécanismes moléculaires impliqués dans la tumorigenèse et en particulier sur le lien existant entre l’intégrité de l’architecture nucléaire et la stabilité du génomeA close link exists between genome stability and nuclear architecture. Lamins, major component of the nuclear envelope, are involved in many nuclear processes, such as replication, transcription and nuclear architecture. It has been reported than lamins A/C are involved in double strand break repair and telomere stability. However, few studies have been conducted on B-type lamins. Interestingly, it was observed that the accumulation of lamin B1 is found in different tumors. Nevertheless, consequences of its deregulation on genome stability remain poorly documented.During my PhD, I analysed the impact of deregulation of lamin B1 on genome maintenance, including double-strand breaks repair and telomere stability. We were able to demonstrate that overexpression of lamin B1 leads to defect of NHEJ, associated with decrease of the 53BP1 recruitment to DNA damage. We have also shown that lamin B1 interacts directly with 53BP1, a protein involved in the choice of the repair pathway, and that this interaction is regulated upon DNA damage. Indeed, the association between these two proteins is disrupted after damage, in endogenous condition, in contrast this dissociation is not observed after lamin B1 overexpression. The defect of 53BP1 recruitment to DNA damage could account for the decrease in the NHEJ efficiency. Moreover, I have identify the protein domains involved in this interaction. It is interesting to note that overexpression of the interaction domain mimics the overexpression of the full lamin B1. Instead, lamin B1 deleted from this domain has no impact on 53BP1 recruitment and on DNA damage persistence. These data support our hypothesis about the sequestration 53BP1 after overexpression of lamin B1.In parallel, we have demonstrated that the lamin B1 overexpression causes the appearance of diplochromosomes concurrent to an increase of senescence. This phenomenon of endoreduplication can be induced by telomere defects such as dysfunctional or deprotected telomeres. Interestingly, I have observed that lamin B1 overexpression leads telomere damages. We also established that lamin B1 interacts with TRF2, a protein of "shelterin" complex involved in the protection against the DNA damage signaling at telomere. The putative retention TRF2 by lamin B1 could cause telomere defects observed after overexpression of the latter.This study identifies new roles of lamin B1 in maintaining genome stability, including through its interactions with two key proteins in the repair of double-strand breaks and stability of telomeres. This opens up new ways of research that will enable a better understanding of the molecular mechanisms involved in tumorigenesis and in particular on the relationship between the integrity of the nuclear architecture and genome stability
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Anglada, Pons Teresa. "Contribució de BRCA1 i 53BP1 a la reparació dels trencaments del DNA: efecte de l’edat." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/666887.
Full textAbstract:
Els organismes han desenvolupat mecanismes eficients per reparar les lesions que es generen constantment al DNA. No obstant això, la freqüència d’anomalies potencialment oncogèniques, com ara els trencaments de doble cadena (DSBs; Double-Strand Breaks) o les reorganitzacions cromosòmiques, es veu incrementada en les persones de més edat. Alguns autors apunten a que l’acumulació de lesions al DNA amb l’edat podria estar relacionada amb una deficiència en el funcionament de les vies de reparació dels DSBs. Tanmateix, la falta d’evidències que estableixin una causalitat directa i la desconeixença del mecanisme molecular associat han dificultat arribar a una conclusió al respecte.
En aquesta tesi s’ha comparat l’eficiència de reparació dels DSBs en cèl·lules epitelials mamàries humanes (HMECs; Human Mammary Epithelial Cells) provinents de teixits no tumorals de donants joves (<27 anys) i grans (>60 anys). En primer lloc s'ha mesurat la cinètica d'inducció i reparació dels DSBs mitjançant la quantificació del nombre de foci de H2AX després d'irradiar les cèl·lules. Les cèl·lules de donants grans van presentar una freqüència basal de foci de H2AX superior a la de les joves, i un major nombre de foci a tots els temps post-irradiació analitzats (1h, 2h i 24h). La modelització matemàtica de les dades obtingudes va permetre concloure que les cèl·lules derivades de donants joves i grans reparaven els DSBs a una velocitat similar, però que aquestes últimes presentaven un retard en l’inici de la reparació dels DSBs.
Per tal d'aprofundir en el mecanisme responsable d’aquest retard en l’inici de la reparació en les HMECs de donants grans, s’ha avaluat l'activitat de les dues vies principals de reparació dels DSBs: la HR (Homologous Recombination) i la c-NHEJ (canonical Non-Homologous End-Joining). Les HMECs es van transfectar amb uns plàsmids reporters específicament dissenyats per mesurar l’eficiència d’aquestes vies. Les cèl·lules de donants grans van presentar una disminució en l’activitat, tant de la c-NHEJ com de la HR. Mitjançant l’assaig de western blot es va descartar que aquesta disminució fos deguda a una reducció en la quantitat de les principals proteïnes implicades.
A continuació, es va analitzar l’eficiència del reclutament de les proteïnes involucrades en la tria de la via de reparació del DSBs: BRCA1 i 53BP1, responsables de dirigir la reparació cap a la via de la HR i de la c-NHEJ, respectivament. Es va analitzar el reclutament de BRCA1 als DSBs en cèl·lules CENPF positives, ja que la HR només és activa durant les fases S/G2, i no es van observar diferències relacionades amb l’edat de les donants. En mesurar el reclutament de 53BP1 als DSBs, al llarg de tota la interfase, les cèl·lules provinents de donants grans van presentar una reducció significativa en el reclutament de 53BP1 als DSBs radioinduïts. L’absència de 53BP1 en aquestes cèl·lules afavoreix la formació ectòpica de foci de BRCA1, CtIP i RPA a la fase G1, indicant que alguns dels DSBs estant patint una resecció extensa. Aquest fenomen és especialment perillós en aquesta fase del cicle perquè els trencaments processats no podran ser dirigits a la HR i, en canvi, seran probablement reparats per vies de reparació alternatives que són altament mutagèniques.
En definitiva, el reclutament deficient de 53BP1 en HMECs provinents de donants d’edat avançada comporta una disminució en la reparació dels DSBs per la c-NHEJ i permet el reclutament de BRCA1 i la resecció dels extrems trencats del DNA a la fase G1 per vies alternatives a la c-NHEJ. Això es tradueix en un retard en l’inici de la reparació dels DSBs que probablement promou la formació de reorganitzacions cromosòmiques potencialment oncogèniques.Organisms have developed mechanisms to efficiently repair the lesions that are continuously induced in their DNA. However, it has been described an increased frequency of potentially oncogenic abnormalities, such as DNA double-strand breaks (DSBs) and genome rearrangements, in older individuals. Related to this, some authors have pointed out that a deficiency in the DNA repair mechanisms could be responsible for the observed accumulation of DNA damage with age. Nonetheless, direct causality remains elusive and lack of knowledge of the molecular mechanisms underlying the age-associated repair defect makes it difficult to draw conclusions. In this thesis, the efficiency of DSB repair has been analyzed in Human Mammary Epithelial Cells (HMECs) derived from non-tumoral tissues from young (<27 years old) and aged (>60 years old) donors. First, the kinetics of DSB induction and repair have been evaluated by quantifying the number of H2AX foci after irradiation. Cells from aged donors showed an increased basal frequency of H2AX foci, and the number of H2AX foci was higher than in young donors’ cells at all times after irradiation analyzed (1h, 2h and 24h). Mathematical modelling of the data obtained allowed us to conclude that although the speed of DSB repair is similar for aged and young donors, the former elicit a delay in the firing of the DSB repair mechanisms. In order to explore the mechanisms underlying the delay in DSB repair firing in HMECs from aged donors, the activity of the two main DSB repair pathways -the HR (Homologous Recombination) and the c-NHEJ (canonical Non-Homologous End-Joining)- has been evaluated. To do so, HMECs were transfected with reporter plasmids that are specifically designed to measure the efficiency of these two repair pathways. Cells from aged donors showed a decreased efficiency of both c-NHEJ and HR. Western blot analysis discarded that this decrease was related to reduced levels of the main proteins involved in DSB repair. Next, we analyzed the recruitment efficiency of the proteins involved in DSB repair pathway choice: BRCA1 and 53BP1, primary responsible to direct the repair to the HR and the c-NHEJ, respectively. Because the HR is only active during S/G2 phases, analysis of the recruitment of BRCA1 to DSBs was restricted to CENPF positive cells, and showed no age-associated differences. Instead, 53BP1 recruitment to DSBs was analyzed during the whole interphase and cells from aged donors showed a significant reduction in the recruitment of 53BP1 to radiation-induced DSBs. Absence of 53BP1 favoured the ectopic formation of BRCA1, CtIP and RPA foci, indicating that a fraction of the DSBs in G1 cells from aged donors suffer an extensive end resection. This entails a considerable threat, because the repair of these extensively processed DNA breaks during G1 can no longer be directed to the c-NHEJ nor to the HR repair. Instead, these DSBs would probably be repaired by highly mutagenic alternative pathways. In conclusion, the deficient recruitment of 53BP1 in HMECs from aged donors leads to a decreased repair by the c-NHEJ. Also, it permits the recruitment of BRCA1 to some DSBs while in G1, that results in extensive DNA end resection. Thus, repair of these DSBs must be accomplished by alternative mechanisms other than c-NHEJ. This is translated into a delayed initiation of DSB repair which in turn, probably promotes the generation of potentially oncogenic genome rearrangements with age.
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McVean, Andrew. "Spatiotemporal dynamics of the DNA double strand break marker 53BP1 after exposure to ionising radiation." Thesis, Brunel University, 2012. http://bura.brunel.ac.uk/handle/2438/6975.
Full textAbstract:
53BP1 is known to be involved in the DNA damage response and has been shown to localise into discrete foci at the site of DNA double strand breaks (DSBs) after exposure to ionising radiation (IR). Quantification of radiation induced foci (RIF) at varying times after exposure has been used to assess the induction of DSB and kinetics of their decline, suggestive of repair. In addition, the size and relative nuclear distribution of foci, observed at different times after IR, could provide insights into the dynamics of these foci that may be relevant for understanding mechanisms of chromosome exchange. To assess this human bronchial epithelial (HBEp) cells, which are the primary target for 50% of our average annual radiation exposure, have been irradiated with low linear energy transfer (LET) 60Co γ-rays (0- 2.0 Gy) or 238Pu high LET α-particles (~1α-particle/nucleus LET 121-235 keV/μm). DSB were quantified at various time points (0-24hrs) after IR, stained for 53BP1 and categorised into three sizes (<0.5μm, 0.5 μm-1.0 μm and >1.0μm in diameter).The data generated was used to ask questions on the radiobiological DSB response of HBEp cells (chapter 4), the recruitment of 53BP1 to DSB and the possible dynamics of DSB for repair. In addition, immortalised HBEp cells transfected with 53BP1-GFP fusion protein were irradiated with 60Co γ-rays and analysed to further assess the spatio-temporal aspects of DSB in live cells. After exposure to 2Gy γ-rays peak induction of 53BP1 was observed within 30 min (22foci) with a subsequent decline to sham levels (2 foci) after 24hrs. For the quantification of spatiotemporal dynamics (chapter 5), a bespoke foci analysis tool was developed (chapter 3) to provide detailed measurements of RIF number, size and relative location with greater speed and reliability than manual counting and categorising method. This novel approach to foci analysis provides evidence for limited (<1μm) movement of foci is presented that may support the ICN model for chromosomal exchange aberrations.
Book chapters on the topic "53BP1"
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Groesser, Torsten, Gerald V. Fontenay, Ju Han, Hang Chang, Janice Pluth, and Bahram Parvin. "Quantification of the Dynamics of DNA Repair to Ionizing Radiation via Colocalization of 53BP1 and ɣH2AX." In Computational Biology, 253–63. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-23724-4_14.
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"53BP." In Encyclopedia of Cancer, 465. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_697.
Full textConference papers on the topic "53BP1"
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Aly, A., Q. Yang, E. Bilal, M. Yao, G. Bhanot, D. Toppmeyer, B. Haffty, and S. Ganesan. "Abnormalities of 53BP1 in Basal-Like Breast Cancer." In Abstracts: Thirty-Second Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 10‐13, 2009; San Antonio, TX. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/0008-5472.sabcs-09-1122.
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Yim, Hyungshin, Sang-Uk Woo, Sol-Bi Shin, and Raymond L. Erikson. "Abstract 3773: Plk1-mediated stabilization of 53BP1 suppresses centrosome abnormal amplification." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3773.
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Moreno, Naike Salvador. "Abstract 1404: Regulation of 53BP1 by the structural nuclear protein NuMA." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1404.
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Salvador Moreno, Naike. "Abstract 2755: Regulation of 53BP1 by the structural nuclear protein NuMA." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-2755.
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He, Chunyan. "Abstract LB-416: Genetic variants in the 53BP1 gene and risk of skin cancer." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-lb-416.
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Nussenzweig, A., and E. Callen. "Abstract ES01-2: 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions." In Abstracts: Thirty-Sixth Annual CTRC-AACR San Antonio Breast Cancer Symposium - Dec 10-14, 2013; San Antonio, TX. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/0008-5472.sabcs13-es01-2.
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Fenton, Amanda L., Diana Tran, and Christine Anne Koch. "Abstract 3955: 53BP1 facilitates the ATM-dependent phosphorylation of APLF in the DNA damage response." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-3955.
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Nacson, Joseph, Andrea Bernhardy, Xiang Hua, Yifan Wang, John Krais, and Neil Johnson. "Abstract A07: 53BP1-driven homologous recombination and PARP inhibitor resistance requires intact BRCA1-PALB2 association." In Abstracts: AACR Special Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; October 1-4, 2017; Pittsburgh, PA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1557-3265.ovca17-a07.
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Jacot, William, Simon Thezenas, Anne-Claire Laberenne, Romain Senal, Cathy Viglianti, Frédéric Bibeau, Jean-Pierre Bleuse, Gilles Romieu, and Pierre-Jean Lamy. "Abstract 1770: Frequent BRCA1 promoter methylation and low 53BP1 status in sporadic triple-negative breast cancer." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-1770.
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Cuella-Martin, Raquel, Catarina Oliveira, Helen E. Lockstone, Suzanne Snellenberg, Natalia Grolmusova, and J. Ross Chapman. "Abstract PR20: A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms." In Abstracts: AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; November 2-5, 2016; Montreal, QC, Canada. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1557-3125.dnarepair16-pr20.
Full textReports on the topic "53BP1"
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Ward, Irene M. Functional Analysis of Interactions Between 53BP1, BRCA1 and p53. Fort Belvoir, VA: Defense Technical Information Center, July 2004. http://dx.doi.org/10.21236/ada429610.
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Ward, Irene M. Functional Analysis of Interactions Between 53BP1, BRCA1 and p53. Fort Belvoir, VA: Defense Technical Information Center, July 2003. http://dx.doi.org/10.21236/ada418734.
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Wang, Bin, and Stephan Elledge. Involvement of 53BP1, a p53 Binding Protein, in Chk2 Phosphorylation of p53 and DNA Damage Cell Cycle Checkpoints. Fort Belvoir, VA: Defense Technical Information Center, May 2004. http://dx.doi.org/10.21236/ada426338.
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Wang, Bin, and Stephen J. Elledge. Involvement of 53BP1, a p43 Binding Protein, in Chk2 Phosphorylation of p53 and DNA Damage Cell Cycle Checkpoints. Fort Belvoir, VA: Defense Technical Information Center, May 2003. http://dx.doi.org/10.21236/ada417278.
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