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Journal articles on the topic 'Fork reversal'

Author: Grafiati

Published: 9 March 2023

Last updated: 19 July 2025

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1

Liu, Wenpeng, Yuichiro Saito, Jessica Jackson, et al. "RAD51 bypasses the CMG helicase to promote replication fork reversal." Science 380, no. 6643 (2023): 382–87. http://dx.doi.org/10.1126/science.add7328.

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Replication fork reversal safeguards genome integrity as a replication stress response. DNA translocases and the RAD51 recombinase catalyze reversal. However, it remains unknown why RAD51 is required and what happens to the replication machinery during reversal. We find that RAD51 uses its strand exchange activity to circumvent the replicative helicase, which remains bound to the stalled fork. RAD51 is not required for fork reversal if the helicase is unloaded. Thus, we propose that RAD51 creates a parental DNA duplex behind the helicase that is used as a substrate by the DNA translocases for branch migration to create a reversed fork structure. Our data explain how fork reversal happens while maintaining the helicase in a position poised to restart DNA synthesis and complete genome duplication.

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2

Sewilam, Reham S., Megan R. Reed, and Robert L. Eoff. "Abstract 1488: DNA polymerase kappa slows replication fork speed by promoting fork reversal in glioblastoma." Cancer Research 85, no. 8_Supplement_1 (2025): 1488. https://doi.org/10.1158/1538-7445.am2025-1488.

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Abstract Replication fork stalling in response to replication stress triggers the activation of replication stressresponse (RSR) pathways to facilitate repair and restart replication processes, including fork reversal andtranslesion DNA synthesis (TLS). During fork reversal, the replication fork undergoes a structural rearrangementto form a four-stranded structure, known as a “chicken foot, ” which helps regulate fork speed by recruitment ofdifferent fork reversal factors, including HLTF, and SMARCAL1. Optimal replication conditions ensure a relativelyconstant and rapid fork progression rate, which is essential for timely genome duplication. TLS requiresspecialized DNA polymerases that assist fork progression by promoting direct bypass of replication blocks. Inglioblastoma, the most aggressive and resistant form of brain cancer, the TLS polymerase kappa (Pol κ) isoverexpressed. This overexpression causes resistance to standard therapeutics and is associated with poorprognosis. A major goal of our study is to understand how Pol κ protects glioma cells from endogenous oncogenicstressors and the DNA-damaging effects of chemotherapeutics. Results from Eoff lab indicate that Pol κ slowsreplication fork speed in glioma cells (T98G, U118-MG) without significantly affecting non-glioma cells (HAP-1, U2OS, RPE). We hypothesized that Pol κ slows replication fork speed by promoting fork reversal in glioma cells.To test this hypothesis, we used a proximity ligation assay (PLA) to verify the colocalization of fork reversalfactors SMARACL1, and HLTF to sites of DNA synthesis in glioma cells. PLA measures the proximity betweenproteins and newly synthesized DNA labeled with nucleotide analog 5-ethynyl-2′-deoxyuridine (EdU), indicatingtheir potential interaction or colocalization, as evidenced by the appearance of fluorescent foci. EdU-SMARCAL1, or EdU-HLTF PLA foci were increased in T98G WT without a significant increase in POLK KO T98G cellsfollowing treatment with 50 nM CPT with no considerable increase in POLK KO T98G cells. These resultssuggest that Pol κ has a role in promoting the colocalization of fork reversal proteins to sites of DNA synthesisin T98G (glioma) cells. To support this conclusion and to study how this affects fork speed, we used DNA fiberspreading (DFS) to determine fork speed with/without depletion of the fork reversal factor SMARCAL1 and HLTF.Depletion of SMARCAL1 and HLTF produced longer IdU tracts in T98G WT cells, indicating faster fork speed.The fork acceleration phenotype in POLK-KO T98G cells remained unaffected by the knock-down ofSMARCAL1, suggesting that these proteins work in the same pathway to regulate fork dynamics in glioblastomacells. These results are the first to establish a link between Pol κ and fork reversal, helping to explain how glioma-specific mechanisms tolerate high rates of DNA damage in the tumor microenvironment. Citation Format: Reham S. Sewilam, Megan R. Reed, Robert L. Eoff. DNA polymerase kappa slows replication fork speed by promoting fork reversal in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1488.

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3

Bhat, Kamakoti P., and David Cortez. "RPA and RAD51: fork reversal, fork protection, and genome stability." Nature Structural & Molecular Biology 25, no. 6 (2018): 446–53. http://dx.doi.org/10.1038/s41594-018-0075-z.

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4

Fierro-Fernandez, M., P. Hernandez, D. B. Krimer, A. Stasiak, and J. B. Schvartzman. "Topological locking restrains replication fork reversal." Proceedings of the National Academy of Sciences 104, no. 5 (2007): 1500–1505. http://dx.doi.org/10.1073/pnas.0609204104.

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5

Quinet, Annabel, Delphine Lemaçon, and Alessandro Vindigni. "Replication Fork Reversal: Players and Guardians." Molecular Cell 68, no. 5 (2017): 830–33. http://dx.doi.org/10.1016/j.molcel.2017.11.022.

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6

Thakar, Tanay, and George-Lucian Moldovan. "The emerging determinants of replication fork stability." Nucleic Acids Research 49, no. 13 (2021): 7224–38. http://dx.doi.org/10.1093/nar/gkab344.

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Abstract A universal response to replication stress is replication fork reversal, where the nascent complementary DNA strands are annealed to form a protective four-way junction allowing forks to avert DNA damage while replication stress is resolved. However, reversed forks are in turn susceptible to nucleolytic digestion of the regressed nascent DNA arms and rely on dedicated mechanisms to protect their integrity. The most well studied fork protection mechanism involves the BRCA pathway and its ability to catalyze RAD51 nucleofilament formation on the reversed arms of stalled replication forks. Importantly, the inability to prevent the degradation of reversed forks has emerged as a hallmark of BRCA deficiency and underlies genome instability and chemosensitivity in BRCA-deficient cells. In the past decade, multiple factors underlying fork stability have been discovered. These factors either cooperate with the BRCA pathway, operate independently from it to augment fork stability in its absence, or act as enablers of fork degradation. In this review, we examine these novel determinants of fork stability, explore the emergent conceptual underpinnings underlying fork protection, as well as the impact of fork protection on cellular viability and cancer therapy.

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7

Liu, W., A. Krishnamoorthy, R. Zhao, and D. Cortez. "Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors." Science Advances 6, no. 46 (2020): eabc3598. http://dx.doi.org/10.1126/sciadv.abc3598.

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Fork reversal is a common response to replication stress, but it generates a DNA end that is susceptible to degradation. Many fork protection factors block degradation, but how they work remains unclear. Here, we find that 53BP1 protects forks from DNA2-mediated degradation in a cell type–specific manner. Fork protection by 53BP1 reduces S-phase DNA damage and hypersensitivity to replication stress. Unlike BRCA2, FANCD2, and ABRO1 that protect reversed forks generated by SMARCAL1, ZRANB3, and HLTF, 53BP1 protects forks remodeled by FBH1. This property is shared by the fork protection factors FANCA, FANCC, FANCG, BOD1L, and VHL. RAD51 is required to generate the resection substrate in all cases. Unexpectedly, BRCA2 is also required for fork degradation in the FBH1 pathway or when RAD51 activity is partially compromised. We conclude that there are multiple fork protection mechanisms that operate downstream of at least two RAD51-dependent fork remodeling pathways.

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8

Batenburg, Nicole L., Sofiane Y. Mersaoui, John R. Walker, et al. "Cockayne syndrome group B protein regulates fork restart, fork progression and MRE11-dependent fork degradation in BRCA1/2-deficient cells." Nucleic Acids Research 49, no. 22 (2021): 12836–54. http://dx.doi.org/10.1093/nar/gkab1173.

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Abstract Cockayne syndrome group B (CSB) protein has been implicated in the repair of a variety of DNA lesions that induce replication stress. However, little is known about its role at stalled replication forks. Here, we report that CSB is recruited to stalled forks in a manner dependent upon its T1031 phosphorylation by CDK. While dispensable for MRE11 association with stalled forks in wild-type cells, CSB is required for further accumulation of MRE11 at stalled forks in BRCA1/2-deficient cells. CSB promotes MRE11-mediated fork degradation in BRCA1/2-deficient cells. CSB possesses an intrinsic ATP-dependent fork reversal activity in vitro, which is activated upon removal of its N-terminal region that is known to autoinhibit CSB’s ATPase domain. CSB functions similarly to fork reversal factors SMARCAL1, ZRANB3 and HLTF to regulate slowdown in fork progression upon exposure to replication stress, indicative of a role of CSB in fork reversal in vivo. Furthermore, CSB not only acts epistatically with MRE11 to facilitate fork restart but also promotes RAD52-mediated break-induced replication repair of double-strand breaks arising from cleavage of stalled forks by MUS81 in BRCA1/2-deficient cells. Loss of CSB exacerbates chemosensitivity in BRCA1/2-deficient cells, underscoring an important role of CSB in the treatment of cancer lacking functional BRCA1/2.

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9

Torres, Rubén, Carolina Gándara, Begoña Carrasco, Ignacio Baquedano, Silvia Ayora, and Juan C. Alonso. "DisA Limits RecG Activities at Stalled or Reversed Replication Forks." Cells 10, no. 6 (2021): 1357. http://dx.doi.org/10.3390/cells10061357.

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The DNA damage checkpoint protein DisA and the branch migration translocase RecG are implicated in the preservation of genome integrity in reviving haploid Bacillus subtilis spores. DisA synthesizes the essential cyclic 3′, 5′-diadenosine monophosphate (c-di-AMP) second messenger and such synthesis is suppressed upon replication perturbation. In vitro, c-di-AMP synthesis is suppressed when DisA binds DNA structures that mimic stalled or reversed forks (gapped forks or Holliday junctions [HJ]). RecG, which does not form a stable complex with DisA, unwinds branched intermediates, and in the presence of a limiting ATP concentration and HJ DNA, it blocks DisA-mediated c-di-AMP synthesis. DisA pre-bound to a stalled or reversed fork limits RecG-mediated ATP hydrolysis and DNA unwinding, but not if RecG is pre-bound to stalled or reversed forks. We propose that RecG-mediated fork remodeling is a genuine in vivo activity, and that DisA, as a molecular switch, limits RecG-mediated fork reversal and fork restoration. DisA and RecG might provide more time to process perturbed forks, avoiding genome breakage.

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10

Le Masson, Marie, Zeynep Baharoglu, and Bénédicte Michel. "ruvAandruvBmutants specifically impaired for replication fork reversal." Molecular Microbiology 70, no. 2 (2008): 537–48. http://dx.doi.org/10.1111/j.1365-2958.2008.06431.x.

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11

De Septenville, Anne L., Stéphane Duigou, Hasna Boubakri, and Bénédicte Michel. "Replication Fork Reversal after Replication–Transcription Collision." PLoS Genetics 8, no. 4 (2012): e1002622. http://dx.doi.org/10.1371/journal.pgen.1002622.

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12

Zellweger, Ralph, Damian Dalcher, Karun Mutreja, et al. "Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells." Journal of Cell Biology 208, no. 5 (2015): 563–79. http://dx.doi.org/10.1083/jcb.201406099.

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Replication fork reversal protects forks from breakage after poisoning of Topoisomerase 1. We here investigated fork progression and chromosomal breakage in human cells in response to a panel of sublethal genotoxic treatments, using other topoisomerase poisons, DNA synthesis inhibitors, interstrand cross-linking inducers, and base-damaging agents. We used electron microscopy to visualize fork architecture under these conditions and analyzed the association of specific molecular features with checkpoint activation. Our data identify replication fork uncoupling and reversal as global responses to genotoxic treatments. Both events are frequent even after mild treatments that do not affect fork integrity, nor activate checkpoints. Fork reversal was found to be dependent on the central homologous recombination factor RAD51, which is consistently present at replication forks independently of their breakage, and to be antagonized by poly (ADP-ribose) polymerase/RECQ1-regulated restart. Our work establishes remodeling of uncoupled forks as a pivotal RAD51-regulated response to genotoxic stress in human cells and as a promising target to potentiate cancer chemotherapy.

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13

Krishnamoorthy, Archana, Jessica Jackson, Taha Mohamed, Madison Adolph, Alessandro Vindigni, and David Cortez. "RADX prevents genome instability by confining replication fork reversal to stalled forks." Molecular Cell 81, no. 14 (2021): 3007–17. http://dx.doi.org/10.1016/j.molcel.2021.05.014.

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14

Thangavel, Saravanabhavan, Matteo Berti, Maryna Levikova, et al. "DNA2 drives processing and restart of reversed replication forks in human cells." Journal of Cell Biology 208, no. 5 (2015): 545–62. http://dx.doi.org/10.1083/jcb.201406100.

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Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5′-to-3′ polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors.

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15

Couch, Frank B., and David Cortez. "Fork reversal, too much of a good thing." Cell Cycle 13, no. 7 (2014): 1049–50. http://dx.doi.org/10.4161/cc.28212.

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16

Sogo, J. M. "Fork Reversal and ssDNA Accumulation at Stalled Replication Forks Owing to Checkpoint Defects." Science 297, no. 5581 (2002): 599–602. http://dx.doi.org/10.1126/science.1074023.

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17

Cotta-Ramusino, Cecilia, Daniele Fachinetti, Chiara Lucca, et al. "Exo1 Processes Stalled Replication Forks and Counteracts Fork Reversal in Checkpoint-Defective Cells." Molecular Cell 17, no. 1 (2005): 153–59. http://dx.doi.org/10.1016/j.molcel.2004.11.032.

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18

Jain, Chetan K., Swagata Mukhopadhyay, and Agneyo Ganguly. "RecQ Family Helicases in Replication Fork Remodeling and Repair: Opening New Avenues towards the Identification of Potential Targets for Cancer Chemotherapy." Anti-Cancer Agents in Medicinal Chemistry 20, no. 11 (2020): 1311–26. http://dx.doi.org/10.2174/1871520620666200518082433.

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Replication fork reversal and restart has gained immense interest as a central response mechanism to replication stress following DNA damage. Although the exact mechanism of fork reversal has not been elucidated precisely, the involvement of diverse pathways and different factors has been demonstrated, which are central to this phenomenon. RecQ helicases known for their vital role in DNA repair and maintaining genome stability has recently been implicated in the restart of regressed replication forks. Through interaction with vital proteins like Poly (ADP) ribose polymerase 1 (PARP1), these helicases participate in the replication fork reversal and restart phenomenon. Most therapeutic agents used for cancer chemotherapy act by causing DNA damage in replicating cells and subsequent cell death. These DNA damages can be repaired by mechanisms involving fork reversal as the key phenomenon eventually reducing the efficacy of the therapeutic agent. Hence the factors contributing to this repair process can be good selective targets for developing more efficient chemotherapeutic agents. In this review, we have discussed in detail the role of various proteins in replication fork reversal and restart with special emphasis on RecQ helicases. Involvement of other proteins like PARP1, recombinase rad51, SWI/SNF complex has also been discussed. Since RecQ helicases play a central role in the DNA damage response following chemotherapeutic treatment, we propose that targeting these helicases can emerge as an alternative to available intervention strategies. We have also summarized the current research status of available RecQ inhibitors and siRNA based therapeutic approaches that targets RecQ helicases. In summary, our review gives an overview of the DNA damage responses involving replication fork reversal and provides new directions for the development of more efficient and sustainable chemotherapeutic approaches.

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19

Warren, Garrett, Richard Stein, Hassane Mchaourab, and Brandt Eichman. "Movement of the RecG Motor Domain upon DNA Binding Is Required for Efficient Fork Reversal." International Journal of Molecular Sciences 19, no. 10 (2018): 3049. http://dx.doi.org/10.3390/ijms19103049.

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RecG catalyzes reversal of stalled replication forks in response to replication stress in bacteria. The protein contains a fork recognition (“wedge”) domain that binds branched DNA and a superfamily II (SF2) ATPase motor that drives translocation on double-stranded (ds)DNA. The mechanism by which the wedge and motor domains collaborate to catalyze fork reversal in RecG and analogous eukaryotic fork remodelers is unknown. Here, we used electron paramagnetic resonance (EPR) spectroscopy to probe conformational changes between the wedge and ATPase domains in response to fork DNA binding by Thermotoga maritima RecG. Upon binding DNA, the ATPase-C lobe moves away from both the wedge and ATPase-N domains. This conformational change is consistent with a model of RecG fully engaged with a DNA fork substrate constructed from a crystal structure of RecG bound to a DNA junction together with recent cryo-electron microscopy (EM) structures of chromatin remodelers in complex with dsDNA. We show by mutational analysis that a conserved loop within the translocation in RecG (TRG) motif that was unstructured in the RecG crystal structure is essential for fork reversal and DNA-dependent conformational changes. Together, this work helps provide a more coherent model of fork binding and remodeling by RecG and related eukaryotic enzymes.

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20

Grompone, Gianfranco, Dusko Ehrlich, and Bénédicte Michel. "Cells defective for replication restart undergo replication fork reversal." EMBO reports 5, no. 6 (2004): 607–12. http://dx.doi.org/10.1038/sj.embor.7400167.

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21

Atkinson, J., and P. McGlynn. "Replication fork reversal and the maintenance of genome stability." Nucleic Acids Research 37, no. 11 (2009): 3475–92. http://dx.doi.org/10.1093/nar/gkp244.

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22

Bhattacharjee, Somendra M. "Interfacial instability and DNA fork reversal by repair proteins." Journal of Physics: Condensed Matter 22, no. 15 (2010): 155102. http://dx.doi.org/10.1088/0953-8984/22/15/155102.

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23

Singleton, Martin R., Sarah Scaife, and Dale B. Wigley. "Structural Analysis of DNA Replication Fork Reversal by RecG." Cell 107, no. 1 (2001): 79–89. http://dx.doi.org/10.1016/s0092-8674(01)00501-3.

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24

Olavarrieta, L. "Supercoiling, knotting and replication fork reversal in partially replicated plasmids." Nucleic Acids Research 30, no. 3 (2002): 656–66. http://dx.doi.org/10.1093/nar/30.3.656.

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25

Graham, Ambassador Thomas, and Douglas B. Shaw. "Nearing a fork in the road: Proliferation or nuclear reversal?" Nonproliferation Review 6, no. 1 (1998): 70–76. http://dx.doi.org/10.1080/10736709808436736.

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26

Ray Chaudhuri, Arnab, Yoshitami Hashimoto, Raquel Herrador, et al. "Topoisomerase I poisoning results in PARP-mediated replication fork reversal." Nature Structural & Molecular Biology 19, no. 4 (2012): 417–23. http://dx.doi.org/10.1038/nsmb.2258.

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27

Chen, Bo-Ruei, Annabel Quinet, Andrea K. Byrum, et al. "XLF and H2AX function in series to promote replication fork stability." Journal of Cell Biology 218, no. 7 (2019): 2113–23. http://dx.doi.org/10.1083/jcb.201808134.

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XRCC4-like factor (XLF) is a non-homologous end joining (NHEJ) DNA double strand break repair protein. However, XLF deficiency leads to phenotypes in mice and humans that are not necessarily consistent with an isolated defect in NHEJ. Here we show that XLF functions during DNA replication. XLF undergoes cell division cycle 7–dependent phosphorylation; associates with the replication factor C complex, a critical component of the replisome; and is found at replication forks. XLF deficiency leads to defects in replication fork progression and an increase in fork reversal. The additional loss of H2AX, which protects DNA ends from resection, leads to a requirement for ATR to prevent an MRE11-dependent loss of newly synthesized DNA and activation of DNA damage response. Moreover, H2ax−/−:Xlf−/− cells exhibit a marked dependence on the ATR kinase for survival. We propose that XLF and H2AX function in series to prevent replication stress induced by the MRE11-dependent resection of regressed arms at reversed replication forks.

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28

Khanduja, Jasbeer Singh, and K. Muniyappa. "Functional Analysis of DNA Replication Fork Reversal Catalyzed byMycobacterium tuberculosisRuvAB Proteins." Journal of Biological Chemistry 287, no. 2 (2011): 1345–60. http://dx.doi.org/10.1074/jbc.m111.304741.

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29

Neelsen, Kai J., and Massimo Lopes. "Replication fork reversal in eukaryotes: from dead end to dynamic response." Nature Reviews Molecular Cell Biology 16, no. 4 (2015): 207–20. http://dx.doi.org/10.1038/nrm3935.

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30

Amunugama, Ravindra, Smaranda Willcox, R. Alex Wu, et al. "Replication Fork Reversal during DNA Interstrand Crosslink Repair Requires CMG Unloading." Cell Reports 23, no. 12 (2018): 3419–28. http://dx.doi.org/10.1016/j.celrep.2018.05.061.

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31

Mutreja, Karun, Jana Krietsch, Jeannine Hess, et al. "ATR-Mediated Global Fork Slowing and Reversal Assist Fork Traverse and Prevent Chromosomal Breakage at DNA Interstrand Cross-Links." Cell Reports 24, no. 10 (2018): 2629–42. http://dx.doi.org/10.1016/j.celrep.2018.08.019.

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32

Mayle, Ryan, Lance Langston, Kelly R. Molloy, Dan Zhang, Brian T. Chait, and Michael E. O’Donnell. "Mcm10 has potent strand-annealing activity and limits translocase-mediated fork regression." Proceedings of the National Academy of Sciences 116, no. 3 (2018): 798–803. http://dx.doi.org/10.1073/pnas.1819107116.

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The 11-subunit eukaryotic replicative helicase CMG (Cdc45, Mcm2-7, GINS) tightly binds Mcm10, an essential replication protein in all eukaryotes. Here we show that Mcm10 has a potent strand-annealing activity both alone and in complex with CMG. CMG-Mcm10 unwinds and then reanneals single strands soon after they have been unwound in vitro. Given the DNA damage and replisome instability associated with loss of Mcm10 function, we examined the effect of Mcm10 on fork regression. Fork regression requires the unwinding and pairing of newly synthesized strands, performed by a specialized class of ATP-dependent DNA translocases. We show here that Mcm10 inhibits fork regression by the well-known fork reversal enzyme SMARCAL1. We propose that Mcm10 inhibits the unwinding of nascent strands to prevent fork regression at normal unperturbed replication forks, either by binding the fork junction to form a block to SMARCAL1 or by reannealing unwound nascent strands to their parental template. Analysis of the CMG-Mcm10 complex by cross-linking mass spectrometry reveals Mcm10 interacts with six CMG subunits, with the DNA-binding region of Mcm10 on the N-face of CMG. This position on CMG places Mcm10 at the fork junction, consistent with a role in regulating fork regression.

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Quinet, Annabel, Stephanie Tirman, Jessica Jackson, et al. "PRIMPOL-Mediated Adaptive Response Suppresses Replication Fork Reversal in BRCA-Deficient Cells." Molecular Cell 77, no. 3 (2020): 461–74. http://dx.doi.org/10.1016/j.molcel.2019.10.008.

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34

Guarino, Estrella, Israel Salguero, Alfonso Jiménez-Sánchez, and Elena C. Guzmán. "Double-Strand Break Generation under Deoxyribonucleotide Starvation in Escherichia coli." Journal of Bacteriology 189, no. 15 (2007): 5782–86. http://dx.doi.org/10.1128/jb.00411-07.

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ABSTRACT Stalled replication forks produced by three different ways of depleting deoxynucleoside triphosphate showed different capacities to undergo “replication fork reversal.” This reaction occurred at the stalled forks generated by hydroxyurea treatment, was impaired under thermal inactivation of ribonucleoside reductase, and did not take place under thymine starvation.

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35

Honda, Masayoshi, Emeleeta A. Paintsil, and Maria Spies. "RAD52 DNA Repair Protein is a Gatekeeper that Protects DNA Replication Forks from Regression by Fork Reversal Motors." Biophysical Journal 118, no. 3 (2020): 160a. http://dx.doi.org/10.1016/j.bpj.2019.11.988.

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36

Shao, Jieya, Mari Iwase, Rong Xu, and Shuyang Lin. "Abstract B017: VCP extracts the chromatin remodeler SNF2H from nascent DNA to stabilize stressed replication forks." Cancer Research 84, no. 1_Supplement (2024): B017. http://dx.doi.org/10.1158/1538-7445.dnarepair24-b017.

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Abstract Valosin-containing protein (VCP) is an evolutionarily conserved AAA+ ATPase which plays pleiotropic roles in global proteostasis by extracting polyubiquitinated proteins from various cellular organelles and structures and facilitating their turnover. Our recent work demonstrated that nuclear VCP activity during DNA damage response specifically depends on ATM/ATR/DNA-PK-mediated Ser784 phosphorylation. Ser784phosphorylation increases VCP ability to facilitate chromatin-associated protein degradation and is required for DNA repair, checkpoint signaling, and cell survival. Clinically, high nuclear pSer784-VCP levels are significantly associated with poor survival outcome among chemotherapy-treated breast and pancreatic cancer patients. Thus, pSer784-VCP is a broadly important and therapeutically relevant genome stabilizer. Here, we focused specifically on the role of pSer784-VCP in DNA replication fork stability during stress, a known source of DNA damage if not properly regulated. By performing single-molecule DNA fiber analysis using human cell lines with genetic gain and loss-of-function of VCP, we observed that VCP protects nascent DNA from hydroxyurea (HU)-induced over-resection and this activity requires Ser784 phosphorylation. Using proximity ligation assay (PLA), we detected HU-induced pSer784-VCP on nascent DNA, suggesting that it may protect stressed forks by extracting functionally important regulators. Consistent with this theory, we detected an interaction of pSer784-VCP with SNF2H, a nucleosome-sliding enzyme which we recently found essential for nascent DNA over-resection at unprotected forks. In support of the hypothesis that SNF2H is a novel substrate of pSer784-VCP at stressed forks, we observed SNF2H retention on nascent DNA upon VCP knockdown in HU-treated cells, and the functional rescue of SNF2H retention by VCP re-expression requires Ser784phosphorylation. In support of their epistatic relationship, SNF2H depletion fully rescued fork over-resection caused by VCP loss. Similarly, blocking fork reversal by depleting SMARCAL1 or FBH1 also rescued fork over-resection caused by VCP loss. Importantly, mutating the ATPase activity of SNF2H abolished its ability to promote fork over-resection, suggesting that nucleosome remodeling by SNF2H underlies its effect on fork stability and may be a key molecular event enabling fork reversal upstream of fork degradation. Collectively, our data suggest that pSer784-VCP is a previously unrecognized stabilizer of stressed DNA replication forks, and it does so at least in part via its physical extraction of SNF2H from nascent DNA and the consequent attenuation of nucleosome remodeling needed for fork reversal and over-resection. More experiments are currently underway to further dissect the mechanistic aspects of this working model as well as to evaluate the potential of developing pSer784-VCP into a clinically relevant chemo-predictive biomarker and chemo-sensitizing target for different types of cancer. Citation Format: Jieya Shao, Mari Iwase, Rong Xu, Shuyang Lin. VCP extracts the chromatin remodeler SNF2H from nascent DNA to stabilize stressed replication forks [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B017.

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Saldanha, Joanne, Julie Rageul, Jinal A. Patel, and Hyungjin Kim. "The Adaptive Mechanisms and Checkpoint Responses to a Stressed DNA Replication Fork." International Journal of Molecular Sciences 24, no. 13 (2023): 10488. http://dx.doi.org/10.3390/ijms241310488.

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DNA replication is a tightly controlled process that ensures the faithful duplication of the genome. However, DNA damage arising from both endogenous and exogenous assaults gives rise to DNA replication stress associated with replication fork slowing or stalling. Therefore, protecting the stressed fork while prompting its recovery to complete DNA replication is critical for safeguarding genomic integrity and cell survival. Specifically, the plasticity of the replication fork in engaging distinct DNA damage tolerance mechanisms, including fork reversal, repriming, and translesion DNA synthesis, enables cells to overcome a variety of replication obstacles. Furthermore, stretches of single-stranded DNA generated upon fork stalling trigger the activation of the ATR kinase, which coordinates the cellular responses to replication stress by stabilizing the replication fork, promoting DNA repair, and controlling cell cycle and replication origin firing. Deregulation of the ATR checkpoint and aberrant levels of chronic replication stress is a common characteristic of cancer and a point of vulnerability being exploited in cancer therapy. Here, we discuss the various adaptive responses of a replication fork to replication stress and the roles of ATR signaling that bring fork stabilization mechanisms together. We also review how this knowledge is being harnessed for the development of checkpoint inhibitors to trigger the replication catastrophe of cancer cells.

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Cybulla, Emily, Jessica Jackson, Stephanie Tirman, Annabel Quinet, Delphine Lemacon, and Alessandro Vindigni. "Abstract 803: Identifying a RAD18/UBC13-dependent mechanism of replication fork recovery to modulate chemoresponse in BRCA1-deficient cancers." Cancer Research 82, no. 12_Supplement (2022): 803. http://dx.doi.org/10.1158/1538-7445.am2022-803.

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Abstract Mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 are associated with an increased lifetime risk of breast and ovarian cancers. While the BRCA proteins play a well-established role in double-stranded DNA break repair, recent studies have revealed an emerging role of BRCA1/2 in replication stress response. While replication forks are extensively degraded by nucleases in BRCA-deficient cancer cells, activation of specialized fork recovery mechanisms enables resumption of DNA synthesis and promotes cell survival. My project aims to determine this fork recovery mechanism in BRCA1-deficient cells and to identify potential recovery factors that can be targeted to improve chemotherapeutic response in BRCA1-mutated breast and ovarian cancers. To monitor perturbations in replication fork dynamics on a genome-wide scale, we utilize a DNA fiber assay technique measuring rates of fork recovery and replication fork degradation. In parallel, electron microscopy analysis allows direct visualization of replication fork intermediates. Cell survival assays are employed to test how loss of fork recovery factors impacts cell proliferation and chemotherapeutic response in BRCA1-deficient cells. Our results reveal that RAD18 and UBC13, which catalyze ubiquitination of Proliferating Cellular Nuclear Antigen (PCNA), promote fork recovery in BRCA1-deficient, but not BRCA2-deficient, cancer cells. Previous work has also shown that PCNA polyubiquitination by UBC13 is important for reversed fork formation in BRCA-proficient cells. However, our findings show that extensive degradation of reversed fork substrates still occurs in BRCA1-deficient cells lacking RAD18 or UBC13, indicating that PCNA polyubiquitination is not essential for fork reversal in this genetic background. In addition, loss of RAD18 in BRCA1-deficient cells significantly slows cell proliferation, and UBC13 inhibition further sensitizes cells lacking BRCA1 to the replication stress inducer Hydroxyurea (HU). Based on our findings, we hypothesize that RAD18, UBC13, and PCNA ubiquitination may represent novel targets to improve chemoresponse in BRCA1-deficient cancers that rely on fork recovery mechanisms for survival. Citation Format: Emily Cybulla, Jessica Jackson, Stephanie Tirman, Annabel Quinet, Delphine Lemacon, Alessandro Vindigni. Identifying a RAD18/UBC13-dependent mechanism of replication fork recovery to modulate chemoresponse in BRCA1-deficient cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 803.

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Follonier, Cindy, Judith Oehler, Raquel Herrador, and Massimo Lopes. "Friedreich's ataxia–associated GAA repeats induce replication-fork reversal and unusual molecular junctions." Nature Structural & Molecular Biology 20, no. 4 (2013): 486–94. http://dx.doi.org/10.1038/nsmb.2520.

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Fierro-Fernández, Marta, Pablo Hernández, Dora B. Krimer, and Jorge B. Schvartzman. "Replication Fork Reversal Occurs Spontaneously after Digestion but Is Constrained in Supercoiled Domains." Journal of Biological Chemistry 282, no. 25 (2007): 18190–96. http://dx.doi.org/10.1074/jbc.m701559200.

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Kile, Andrew C., Diana A. Chavez, Julien Bacal, et al. "HLTF’s Ancient HIRAN Domain Binds 3′ DNA Ends to Drive Replication Fork Reversal." Molecular Cell 58, no. 6 (2015): 1090–100. http://dx.doi.org/10.1016/j.molcel.2015.05.013.

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Adolph, Madison, Swati Balakrishnan, Walter Chazin, and David Cortez. "Abstract IA024: Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses." Cancer Research 84, no. 1_Supplement (2024): IA024. http://dx.doi.org/10.1158/1538-7445.dnarepair24-ia024.

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Abstract RAD51 nucleoprotein filaments are central to maintaining genome stability, governing crucial processes like homology-directed double-strand break repair, replication fork reversal, and shielding replication forks from nucleases. The precise regulation of RAD51 filament formation and stability is critical for these functions, which suppress tumorigenesis and determine cellular responses to common cancer therapies. RADX is a pivotal regulator of RAD51 in the context of DNA replication, impacting replication fork reversal and fork stabilization. After identifying RADX as an RPA-related RAD51 regulator, we have worked to understand how it acts, thereby elucidating its role in genome stability and its influence on cancer cell responses to PARP inhibitors and chemotherapies. Genetically, RADX exhibits a dual role, capable of either inhibiting or promoting replication fork reversal based on the levels of replication stress. Biochemical studies show that RADX has inhibitory effects on RAD51 strand exchange and D-loop formation activities, achieved through direct binding to single-strand DNA and RAD51, along with the stimulation of RAD51 ATP hydrolysis. These activities collectively destabilize RAD51 nucleofilaments, opposing the stabilizing effects of BRCA2. Cells lacking RADX regulatory functions exhibit replication defects, DNA damage accumulation, reduced growth, and heightened sensitivity to DNA damage and replication stress. Structural analyses, including cryo-electron microscopy and mass photometry, revealed how RADX binds ssDNA and show it exists in multiple oligomeric states with a preference for trimers when bound to single-stranded DNA. Negative stain electron microscopy imaging supports a model wherein RADX functions by capping and restricting the growing ends of RAD51 filaments. In summary, our findings provide a comprehensive understanding of the regulatory mechanisms governing RAD51 nucleofilament dynamics by RADX, emphasizing its crucial role in coordinating replication fork stability and genome integrity. This knowledge not only contributes to the fundamental understanding of cellular processes but also offers insights into potential therapeutic interventions targeting RAD51-controlled pathways. Citation Format: Madison Adolph, Swati Balakrishnan, Walter Chazin, David Cortez. Mechanistic insights into how RADX regulates RAD51 nucleoprotein filaments to maintain genome stability and control replication stress responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA024.

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Flores, Maria Jose, Vladimir Bidnenko, and Bénédicte Michel. "The DNA repair helicase UvrD is essential for replication fork reversal in replication mutants." EMBO reports 5, no. 10 (2004): 983–88. http://dx.doi.org/10.1038/sj.embor.7400262.

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Dixit, Suruchi, Tarun Nagraj, Debanjali Bhattacharya, et al. "RTEL1 helicase counteracts RAD51-mediated homologous recombination and fork reversal to safeguard replicating genomes." Cell Reports 43, no. 8 (2024): 114594. http://dx.doi.org/10.1016/j.celrep.2024.114594.

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Tian, Tian, Min Bu, Xu Chen, et al. "The ZATT-TOP2A-PICH Axis Drives Extensive Replication Fork Reversal to Promote Genome Stability." Molecular Cell 81, no. 1 (2021): 198–211. http://dx.doi.org/10.1016/j.molcel.2020.11.007.

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Regairaz, Marie, Yong-Wei Zhang, Haiqing Fu, et al. "Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I–DNA complexes." Journal of Cell Biology 195, no. 5 (2011): 739–49. http://dx.doi.org/10.1083/jcb.201104003.

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Deoxyribonucleic acid (DNA) topoisomerases are essential for removing the supercoiling that normally builds up ahead of replication forks. The camptothecin (CPT) Top1 (topoisomerase I) inhibitors exert their anticancer activity by reversibly trapping Top1–DNA cleavage complexes (Top1cc’s) and inducing replication-associated DNA double-strand breaks (DSBs). In this paper, we propose a new mechanism by which cells avoid Top1-induced replication-dependent DNA damage. We show that the structure-specific endonuclease Mus81-Eme1 is responsible for generating DSBs in response to Top1 inhibition and for allowing cell survival. We provide evidence that Mus81 cleaves replication forks rather than excises Top1cc’s. DNA combing demonstrated that Mus81 also allows efficient replication fork progression after CPT treatment. We propose that Mus81 cleaves stalled replication forks, which allows dissipation of the excessive supercoiling resulting from Top1 inhibition, spontaneous reversal of Top1cc, and replication fork progression.

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Neelsen, Kai J., Isabella M. Y. Zanini, Raquel Herrador, and Massimo Lopes. "Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates." Journal of Cell Biology 200, no. 6 (2013): 699–708. http://dx.doi.org/10.1083/jcb.201212058.

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Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle–regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints.

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Walker, John R., and Xu-Dong Zhu. "Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy." International Journal of Molecular Sciences 23, no. 18 (2022): 10212. http://dx.doi.org/10.3390/ijms231810212.

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A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

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Guarino, Estrella, Alfonso Jiménez-Sánchez, and Elena C. Guzmán. "Defective Ribonucleoside Diphosphate Reductase Impairs Replication Fork Progression in Escherichia coli." Journal of Bacteriology 189, no. 9 (2007): 3496–501. http://dx.doi.org/10.1128/jb.01632-06.

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ABSTRACT The observed lengthening of the C period in the presence of a defective ribonucleoside diphosphate reductase has been assumed to be due solely to the low deoxyribonucleotide supply in the nrdA101 mutant strain. We show here that the nrdA101 mutation induces DNA double-strand breaks at the permissive temperature in a recB-deficient background, suggesting an increase in the number of stalled replication forks that could account for the slowing of replication fork progression observed in the nrdA101 strain in a Rec+ context. These DNA double-strand breaks require the presence of the Holliday junction resolvase RuvABC, indicating that they have been generated from stalled replication forks that were processed by the specific reaction named “replication fork reversal.” Viability results supported the occurrence of this process, as specific lethality was observed in the nrdA101 recB double mutant and was suppressed by the additional inactivation of ruvABC. None of these effects seem to be due to the limitation of the deoxyribonucleotide supply in the nrdA101 strain even at the permissive temperature, as we found the same level of DNA double-strand breaks in the nrdA + strain growing under limited (2-μg/ml) or under optimal (5-μg/ml) thymidine concentrations. We propose that the presence of an altered NDP reductase, as a component of the replication machinery, impairs the progression of the replication fork, contributing to the lengthening of the C period in the nrdA101 mutant at the permissive temperature.

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Bai, Gongshi, Chames Kermi, Henriette Stoy, et al. "HLTF Promotes Fork Reversal, Limiting Replication Stress Resistance and Preventing Multiple Mechanisms of Unrestrained DNA Synthesis." Molecular Cell 78, no. 6 (2020): 1237–51. http://dx.doi.org/10.1016/j.molcel.2020.04.031.

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