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Journal articles on the topic 'Synthetic Dosage Lethality'

Author: Grafiati

Published: 2 June 2025

Last updated: 31 July 2025

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1

Kroll, Eugene S., Katherine M. Hyland, Philip Hieter, and Joachim J. Li. "Establishing Genetic Interactions by a Synthetic Dosage Lethality Phenotype." Genetics 143, no. 1 (1996): 95–102. http://dx.doi.org/10.1093/genetics/143.1.95.

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Abstract We have devised a genetic screen, termed synthetic dosage lethality, in which a cloned “reference” gene is inducibly overexpressed in a set of mutant strains carrying potential “target” mutations. To test the specificity of the method, two reference genes, CTF13, encoding a centromere binding protein, and ORC6, encoding a subunit of the origin of replication binding complex, were overexpressed in a large collection of mutants defective in either chromosome segregation or replication. CTF13 overexpression caused synthetic dosage lethality in combination with ctf14-42 (cbf2, ndc10), ctf

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Zimmermann, Christine, Ignacio Garcia, Manja Omerzu, Pierre Chymkowitch, Beibei Zhang, and Jorrit M. Enserink. "Mapping the Synthetic Dosage Lethality Network ofCDK1/CDC28." G3: Genes|Genomes|Genetics 7, no. 6 (2017): 1753–66. http://dx.doi.org/10.1534/g3.117.042317.

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Gupta, Anuradha, Anas Ahmad, Aqib Iqbal Dar, and Rehan Khan. "Synthetic Lethality: From Research to Precision Cancer Nanomedicine." Current Cancer Drug Targets 18, no. 4 (2018): 337–46. http://dx.doi.org/10.2174/1568009617666170630141931.

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Cancer is an evolutionary disease with multiple genetic alterations, accumulated due to chromosomal instability and/or aneuploidy and it sometimes acquires drug-resistant phenotype also. Whole genome sequencing and mutational analysis helped in understanding the differences among persons for predisposition of a disease and its treatment non-responsiveness. Thus, molecular targeted therapies came into existence. Among them, the concept of synthetic lethality have enthralled great attention as it is a pragmatic approach towards exploiting cancer cell specific mutations to specifically kill cance

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Lee, Amanda R., Anna Tangiyan, Isha Singh, and Peter S. Choi. "Incomplete paralog compensation generates selective dependency on TRA2A in cancer." PLOS Genetics 21, no. 5 (2025): e1011685. https://doi.org/10.1371/journal.pgen.1011685.

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Paralogs often exhibit functional redundancy, allowing them to effectively compensate for each other’s loss. However, this buffering mechanism is frequently disrupted in cancer, exposing unique paralog-specific vulnerabilities. Here, we identify a selective dependency on the splicing factor TRA2A. We find that TRA2A and its paralog TRA2B are synthetic lethal partners that function as widespread and largely redundant activators of both alternative and constitutive splicing. While loss of TRA2A alone is typically neutral due to compensation by TRA2B, we discover that a subset of cancer cell line

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Dandage, Rohan, and Elena Kuzmin. "Abstract B012: Predicting targetable paralog synthetic lethalities and functional redundancies in cancer genomes." Molecular Cancer Therapeutics 23, no. 6_Supplement (2024): B012. http://dx.doi.org/10.1158/1538-8514.synthleth24-b012.

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Abstract Paralogs are prevalent in the human genome and are considered a rich source of synthetic lethality due to functional redundancy. For a cancer cell carrying a gene with Loss-Of-Function (LOF) mutation, inactivation of its paralog using gene editing can induce a selective decrease in viability, leaving normal cells that do not harbor the mutation unharmed. Previous studies have exploited this vulnerability of cancer genomes. However, the cancer-specificity of such synthetic lethality limits its application across different cancer types. Furthermore, the role of functional redundancy whi

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Megchelenbrink, Wout, Rotem Katzir, Xiaowen Lu, Eytan Ruppin, and Richard A. Notebaart. "Synthetic dosage lethality in the human metabolic network is highly predictive of tumor growth and cancer patient survival." Proceedings of the National Academy of Sciences 112, no. 39 (2015): 12217–22. http://dx.doi.org/10.1073/pnas.1508573112.

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Synthetic dosage lethality (SDL) denotes a genetic interaction between two genes whereby the underexpression of gene A combined with the overexpression of gene B is lethal. SDLs offer a promising way to kill cancer cells by inhibiting the activity of SDL partners of activated oncogenes in tumors, which are often difficult to target directly. As experimental genome-wide SDL screens are still scarce, here we introduce a network-level computational modeling framework that quantitatively predicts human SDLs in metabolism. For each enzyme pair (A, B) we systematically knock out the flux through A c

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Gilad, Oren, Barzin Y. Nabet, Ryan L. Ragland, et al. "Combining ATR Suppression with Oncogenic Ras Synergistically Increases Genomic Instability, Causing Synthetic Lethality or Tumorigenesis in a Dosage-Dependent Manner." Cancer Research 70, no. 23 (2010): 9693–702. http://dx.doi.org/10.1158/0008-5472.can-10-2286.

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Thu, Yee Mon. "How Not To Be in the Wrong Place at the Wrong Time: An Education Primer for Use with “Deposition of Centromeric Histone H3 Variant CENP-A/Cse4 into Chromatin Is Facilitated by Its C-Terminal Sumoylation”." Genetics 216, no. 2 (2020): 333–42. http://dx.doi.org/10.1534/genetics.120.303493.

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Recent work by Kentaro Ohkuni and colleagues exemplifies how a series of molecular mechanisms contribute to a cellular outcome—equal distribution of chromosomes. Failure to maintain structural and numerical integrity of chromosomes is one contributing factor in genetic diseases such as cancer. Specifically, the authors investigated molecular events surrounding centromeric histone H3 variant Cse4 deposition—a process important for chromosome segregation, using Saccharomyces cerevisiae as a model organism. This study illustrates an example of a post-translational modification—sumoylation—regulat

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Liu, Chang, Dewald van Dyk, Yue Li, Brenda Andrews, and Hai Rao. "A genome-wide synthetic dosage lethality screen reveals multiple pathways that require the functioning of ubiquitin-binding proteins Rad23 and Dsk2." BMC Biology 7, no. 1 (2009): 75. http://dx.doi.org/10.1186/1741-7007-7-75.

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Young, Barry P., Kathryn L. Post, Jesse T. Chao, Fabian Meili, Kurt Haas, and Christopher Loewen. "Sentinel interaction mapping – a generic approach for the functional analysis of human disease gene variants using yeast." Disease Models & Mechanisms 13, no. 7 (2020): dmm044560. http://dx.doi.org/10.1242/dmm.044560.

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ABSTRACTAdvances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here, we describe a generic approach using the yeast Saccharomyces cerevisiae to quickly develop gene-specific in vivo assays that can be used to quantify the level of function of a genetic variant. Using synthetic dosage lethality screening, ‘sentinel’ yeast strains are identified that are sensitive to overexpression of a human disease gene. V

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Hyland, Katherine M., Jeffrey Kingsbury, Doug Koshland, and Philip Hieter. "Ctf19p: A Novel Kinetochore Protein in Saccharomyces cerevisiae and a Potential Link between the Kinetochore and Mitotic Spindle." Journal of Cell Biology 145, no. 1 (1999): 15–28. http://dx.doi.org/10.1083/jcb.145.1.15.

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A genetic synthetic dosage lethality (SDL) screen using CTF13 encoding a known kinetochore protein as the overexpressed reference gene identified two chromosome transmission fidelity (ctf) mutants, YCTF58 and YCTF26. These mutant strains carry independent alleles of a novel gene, which we have designated CTF19. In light of its potential role in kinetochore function, we have cloned and characterized the CTF19 gene in detail. CTF19 encodes a nonessential 369–amino acid protein. ctf19 mutant strains display a severe chromosome missegregation phenotype, are hypersensitive to benomyl, and accumulat

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Nagy, Matthew, Fiorella Schischlik, Kun Wang, et al. "Abstract 3118: Predicting response to PARP inhibitors in pediatric cancer via synthetic lethal networks." Cancer Research 83, no. 7_Supplement (2023): 3118. http://dx.doi.org/10.1158/1538-7445.am2023-3118.

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Abstract Introduction: PARP inhibitors (PARPi) are known to have a synthetic lethal (SL) relationship with BRCA1/2 mutated cancers (ie: BRCA loss confers sensitivity to PARPi), but heterogeneity in response exists. PARPi have also found utility in BRCA-non mutated cancers, suggesting other factors may contribute to response. Recently, PARPi trials in pediatric solid tumors have had mixed results. SL interactions have been shown to exist in a network relationship, as such the aim of this study was to identify a clinically relevant SL signature (including synthetic dosage lethality and synthetic

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Moore, Love A., Akshaya Karthikeyan, Bryan Correa Gonzalez, Anamitra Bhaumik, Ethan Sandoval, and Alan Paul Lombard. "Abstract 377: Mechanistic and phenotypic insights into temporal and dosage-dependent responses to PARP inhibition in advanced prostate cancer." Cancer Research 85, no. 8_Supplement_1 (2025): 377. https://doi.org/10.1158/1538-7445.am2025-377.

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Abstract Background: Poly ADP-ribose polymerase (PARP) inhibition effectively treats prostate cancer (PCa) by inducing replication stress and cell death through synthetic lethality. However, PARP inhibitor (PARPi) resistance inevitably develops, necessitating the study of short- and long-term effects. Responses to PARP inhibition in PCa vary from cytostasis to cell death, with the impact of different dosages and durations underexplored. This study examines how temporal and dosage variations of Olaparib (Ola) influence PCa cell phenotypes and identifies mechanisms underlying treatment response

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Haworth, Justin, Robert C. Alver, Melissa Anderson та Anja-Katrin Bielinsky. "Ubc4 and Not4 Regulate Steady-State Levels of DNA Polymerase-α to Promote Efficient and Accurate DNA Replication". Molecular Biology of the Cell 21, № 18 (2010): 3205–19. http://dx.doi.org/10.1091/mbc.e09-06-0452.

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The accurate duplication of chromosomal DNA is required to maintain genomic integrity. However, from an evolutionary point of view, a low mutation rate during DNA replication is desirable. One way to strike the right balance between accuracy and limited mutagenesis is to use a DNA polymerase that lacks proofreading activity but contributes to DNA replication in a very restricted manner. DNA polymerase-α fits this purpose exactly, but little is known about its regulation at the replication fork. Minichromosome maintenance protein (Mcm) 10 regulates the stability of the catalytic subunit of pol-

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Gao, Dingcheng, Yingzhuo Liu, and Yi Ban. "Abstract 419: Chromosomal instability and oncogene dosage variations underlying KRAS G12C inhibition therapy resistance in lung cancer." Cancer Research 85, no. 8_Supplement_1 (2025): 419. https://doi.org/10.1158/1538-7445.am2025-419.

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Abstract KRAS G12C inhibitors (G12Ci), including the FDA-approved Sotorasib and Adagrasib, represent a significant advancement in targeted cancer therapies. As their use in non-small cell lung cancer patients expands, addressing the pervasive challenge of drug resistance is critical. Resistance mechanisms can be innate, acquired, or both, often coexisting within complex scenarios. Recent studies have highlighted various resistance mechanisms to G12Ci, such as oncogene amplification, activation of alternative signaling pathways, additional mutations in KRAS or its associated networks, and adapt

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Munroe, Marklie, and Jill Kolesar. "Olaparib for the treatment of BRCA-mutated advanced ovarian cancer." American Journal of Health-System Pharmacy 73, no. 14 (2016): 1037–41. http://dx.doi.org/10.2146/ajhp150550.

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Abstract Purpose The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory ovarian cancer, are reviewed. Summary Olaparib (Lynparza, AstraZeneca) is an oral inhibitor of poly(ADP-ribose) polymerase (PARP) proteins that play a key role in DNA repair and genomic stability. Olaparib is indicated for use in treating certain patients with advanced, recurrent ovarian cancer who have mutations of the breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2). In patients with BRCA-mutated can

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Ohkuni, Kentaro, Evelyn Suva, Wei-Chun Au, et al. "Deposition of Centromeric Histone H3 Variant CENP-A/Cse4 into Chromatin Is Facilitated by Its C-Terminal Sumoylation." Genetics 214, no. 4 (2020): 839–54. http://dx.doi.org/10.1534/genetics.120.303090.

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Centromeric localization of CENP-A (Cse4 in Saccharomyces cerevisiae, CID in flies, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of overexpressed CENP-A contributes to aneuploidy in yeast, flies, and humans, and is proposed to promote tumorigenesis in human cancers. Hence, defining molecular mechanisms that promote or prevent mislocalization of CENP-A is an area of active investigation. In budding yeast, evolutionarily conserved histone chaperones Scm3 and chromatin assembly factor-1 (CAF-1) promote localization of Cse4 to centromeric and noncentromeric r

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Eisenstatt, Jessica R., Lars Boeckmann, Wei-Chun Au, et al. "Dbf4-Dependent Kinase (DDK)-Mediated Proteolysis of CENP-A Prevents Mislocalization of CENP-A in Saccharomyces cerevisiae." G3: Genes|Genomes|Genetics 10, no. 6 (2020): 2057–68. http://dx.doi.org/10.1534/g3.120.401131.

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The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Defining mechanisms that prevent mislocalization of CENP-A is an area of active investigation. Ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) by E3 ubiquitin ligases such as Psh1 prevents mislocalization of Cse4, and psh1Δ strains display sy

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Zhang, Haijiao, Basil Allen, Daniel Bottomly, Peter Ryabinin, and Schannon K. Mcweeney. "Abstract A012: Targeting proteasome vulnerabilities for the treatment of monosomy 7 associated blood disorders." Molecular Cancer Therapeutics 23, no. 6_Supplement (2024): A012. http://dx.doi.org/10.1158/1538-8514.synthleth24-a012.

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Abstract Monosomy 7 is among the most frequent cytogenetic abnormalities in hematological disorders and is associated with short survival and drug resistance. Despite its high prevalence and detrimental impact, the therapeutic vulnerabilities underlying monosomy 7-associated blood disorders remain largely elusive, impeding progress toward improved patient care. The homeostatic cellular requirement for a normal dosage of essential genes creates an opportunity to target vulnerabilities that arise due to reduced levels of proteins encoded by a haploinsufficient essential gene. Briefly, the loss o

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Maranda, Vincent, Frederick S. Vizeacoumar, Yue Zhang, Liliia Kyrylenko, Andrew Freywald, and Franco J. Vizeacoumar. "Abstract 5412: Developing combination therapies for telomerase-overexpressing cancers." Cancer Research 85, no. 8_Supplement_1 (2025): 5412. https://doi.org/10.1158/1538-7445.am2025-5412.

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Abstract Cancer heterogeneity poses a significant medical challenge, necessitating therapies tailored not only to individual patients but also to the unique cancer clones that exist within diverse microenvironmental contexts. Despite this diversity, nearly all cancer cells share a reliance on telomeres to maintain genomic stability. The telomerase (hTERT) gene is hyperactive in many cancers and has been identified as a potential target for treatment. While this has led to the development of multiple telomerase-targeting approaches, disappointingly, none have been approved in clinical applicati

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Liu, Zeyu, Zachary A. Secunda, Abiha Abdullah, et al. "Post-Injury Treatment with Rapid Intraosseous Injection of Lyophilized Synthetic Platelets Enhances Survival, Hemostasis, and Hemodynamics in a Rat Model of Liver Laceration." Blood 144, Supplement 1 (2024): 3931. https://doi.org/10.1182/blood-2024-207615.

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Introduction Trauma is the leading cause of death for individuals under 45 years old, with uncontrolled bleeding being a significant contributor to preventable death. Our previous study demonstrated the effectiveness of a bioinspired synthetic platelet (SP) administered intravenously before injury in reducing blood loss in a rabbit liver laceration model (Srinivasan et al., 2024). Building on this, recent development efforts have successfully generated a shelf-stable lyophilized formulation of the synthetic platelets (Lyo-SP). Furthermore, intraosseous (IO) injection is commonly used in pre-ho

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Chang, Kimberly A., and Mitzi I. Kuroda. "Modulation of MSL1 Abundance in Female Drosophila Contributes to the Sex Specificity of Dosage Compensation." Genetics 150, no. 2 (1998): 699–709. http://dx.doi.org/10.1093/genetics/150.2.699.

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Abstract Dosage compensation in Drosophila is the mechanism by which X-linked gene expression is made equal in males and females. Proper regulation of this process is critical to the survival of both sexes. Males must turn the male-specific lethal (msl)-mediated pathway of dosage compensation on and females must keep it off. The msl2 gene is the primary target of negative regulation in females. Preventing production of MSL2 protein is sufficient to prevent dosage compensation; however, ectopic expression of MSL2 protein in females is not sufficient to induce an insurmountable level of dosage c

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Zhou, Feng, Lu Liu, Lei Jiang та ін. "Abstract 4539: ZM-2311 a novel and highly potent Polθ inhibitor demonstrates synergistically anti-tumor activities in combination with different therapeutics". Cancer Research 84, № 6_Supplement (2024): 4539. http://dx.doi.org/10.1158/1538-7445.am2024-4539.

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Abstract Homologous recombination (HR) is a high-fidelity DNA double-strand break (DSB) repair pathway, and its dysfunction leads to cell genome instability and can result in tumorigenesis. In the situation of HR deficiency, DNA polymerase theta (Polθ) mediated microhomology-mediated end joining (MMEJ) is up-regulated to serve as a backup pathway for DSB repair. Several studies have proved that the inhibition of Polθ causes synthetic lethality with HR deficiency, and Polθ emerges as a potential DNA damage repair (DDR) target for the treatment of HR deficient tumors. In addition, there is evide

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Satterfield, Terrence F., Stephen M. Jackson, and Leo J. Pallanck. "A Drosophila Homolog of the Polyglutamine Disease Gene SCA2 Is a Dosage-Sensitive Regulator of Actin Filament Formation." Genetics 162, no. 4 (2002): 1687–702. http://dx.doi.org/10.1093/genetics/162.4.1687.

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Abstract Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in ataxin-2, the SCA2 gene product. The normal cellular function of ataxin-2 and the mechanism by which polyglutamine expansion of ataxin-2 causes neurodegeneration remain unknown. In this study we have used genetic and molecular approaches to investigate the function of a Drosophila homolog of the SCA2 gene (Datx2). Like human ataxin-2, Datx2 is found throughout development in a variety of tissue types and localizes to the cytoplasm. Mutations th

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Kumar, Sanjay, Roopa Rani Samal, Manu Sankar, Sarita Kumar, and Arvind Kumar Shakya. "Methoxyfenozide as a potent insect growth regulator: Disruption of growth, development and chitin synthesis in <i>Aedes aegypti</i> for sustainable vector control." Journal of Applied and Natural Science 17, no. 2 (2025): 951–60. https://doi.org/10.31018/jans.v17i2.6864.

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Aedes aegypti is a major vector of arboviral diseases such as dengue, chikungunya, Zika, and yellow fever. Traditional chemical insecticides have led to widespread insecticide resistance and posed risks to non-target organisms and the environment. Insect growth regulators (IGRs) offer a promising alternative by disrupting mosquito development rather than inducing immediate lethality. The present study evaluated the efficacy of methoxyfenozide, a non-steroidal ecdysteroid agonist, in disrupting the development and chitin synthesis of Ae. aegypti larvae to explore its potential as a mosquito con

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Buggia, Isabella, Franco Locatelli, Mario B. Regazzi, and Marco Zecca. "Busulfan." Annals of Pharmacotherapy 28, no. 9 (1994): 1055–62. http://dx.doi.org/10.1177/106002809402800911.

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OBJECTIVE: To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients. DATA SOURCES: English-language literature published between 1953 and 1993 was analyzed; pertinent literature was reviewed. STUDY SELECTION: Emphasis was placed on pharmacologic studies and clinical trials involving busulfan therapy both in myeloproliferative disorders and in conditioning regimens for autologous or allogeneic bone marrow transplantation. DATA EXTRACTION: Data from both pediatric and adult studies were evaluated;

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Takamoto, Norio, Isao Kurihara, Kevin Lee, Francesco J. DeMayo, Ming-Jer Tsai, and Sophia Y. Tsai. "Haploinsufficiency of Chicken Ovalbumin Upstream Promoter Transcription Factor II in Female Reproduction." Molecular Endocrinology 19, no. 9 (2005): 2299–308. http://dx.doi.org/10.1210/me.2005-0019.

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Abstract The chicken ovalbumin upstream promoter transcription factor II, COUP-TFII, is a member of the orphan nuclear receptor transcription factor family. Genetic ablation of COUP-TFII results in early embryonic lethality and demonstrates that this gene is required for cardiac and vascular development. Expression of COUP-TFII persists throughout postnatal life in various tissues including the female reproductive tract. However, the physiological function of COUP-TFII in female reproduction has not been extensively analyzed. Here, we provide phenotypic evidences that haploinsufficiency of COU

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Zhang, Biyu, Chen Tang, Yanli Yao, et al. "The tumor therapy landscape of synthetic lethality." Nature Communications 12, no. 1 (2021). http://dx.doi.org/10.1038/s41467-021-21544-2.

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AbstractSynthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combi

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Benstead-Hume, Graeme, Sarah K. Wooller, and Frances M. G. Pearl. "Computational Approaches to Identify Genetic Interactions for Cancer Therapeutics." Journal of Integrative Bioinformatics 14, no. 3 (2017). http://dx.doi.org/10.1515/jib-2017-0027.

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AbstractThe development of improved cancer therapies is frequently cited as an urgent unmet medical need. Here we describe how genetic interactions are being therapeutically exploited to identify novel targeted treatments for cancer. We discuss the current methodologies that use ‘omics data to identify genetic interactions, in particular focusing on synthetic sickness lethality (SSL) and synthetic dosage lethality (SDL). We describe the experimental and computational approaches undertaken both in humans and model organisms to identify these interactions. Finally we discuss some of the identifi

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Cunningham, Chelsea E., Frederick S. Vizeacoumar, Yue Zhang, et al. "Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality." Cell Genomics, May 2025, 100876. https://doi.org/10.1016/j.xgen.2025.100876.

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Barrena, Naroa, Flores Carlos Javier Rodriguez, Luis Vitores Valcárcel, et al. "Beyond synthetic lethality in large-scale metabolic and regulatory network models via genetic minimal intervention sets." May 14, 2025. https://doi.org/10.5281/zenodo.15350241.

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Arna, Ananna Bhadra, Hardikkumar Patel, Ravi Shankar Singh, et al. "Synthetic lethal interactions of DEAD/H-box helicases as targets for cancer therapy." Frontiers in Oncology 12 (January 26, 2023). http://dx.doi.org/10.3389/fonc.2022.1087989.

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DEAD/H-box helicases are implicated in virtually every aspect of RNA metabolism, including transcription, pre-mRNA splicing, ribosomes biogenesis, nuclear export, translation initiation, RNA degradation, and mRNA editing. Most of these helicases are upregulated in various cancers and mutations in some of them are associated with several malignancies. Lately, synthetic lethality (SL) and synthetic dosage lethality (SDL) approaches, where genetic interactions of cancer-related genes are exploited as therapeutic targets, are emerging as a leading area of cancer research. Several DEAD/H-box helica

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Gallo, David, Jordan T. F. Young, Jimmy Fourtounis, et al. "CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition." Nature, April 20, 2022. http://dx.doi.org/10.1038/s41586-022-04638-9.

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AbstractAmplification of the CCNE1 locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies1–4. To uncover therapeutic targets for tumours with CCNE1 amplification, we undertook genome-scale CRISPR–Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here we report that increasing CCNE1 dosage engenders a vulnerability to t

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Chatfield-Reed, Kate, Kurtis Marno Jones, Farah Shah, and Gordon Chua. "Genetic-Interaction Screens Uncover Novel Biological Roles and Regulators of Transcription Factors in Fission Yeast." G3 Genes|Genomes|Genetics, August 4, 2022. http://dx.doi.org/10.1093/g3journal/jkac194.

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Abstract In Schizosaccharomyces pombe, systematic analyses of single transcription factor deletion or overexpression strains have made substantial advances in determining the biological roles and target genes of transcription factors, yet these characteristics are still relatively unknown for over a quarter of them. Moreover, the comprehensive list of proteins that regulate transcription factors remains incomplete. To further characterize S. pombe transcription factors, we performed synthetic sick/lethality (SL) and synthetic dosage lethality (SDL) screens by synthetic genetic array (SGA). Exa

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Arnoldus, Tim, Alex van Vliet, Onno B. Bleijerveld, et al. "Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers." Nature Genetics, July 4, 2025. https://doi.org/10.1038/s41588-025-02221-2.

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Abstract Synthetic lethal interactions (SLIs) based on genomic alterations in cancer have been therapeutically explored. We investigated the SLI space as a function of differential RNA expression in cancer and normal tissue. Computational analyses of functional genomic and gene expression resources uncovered a cancer-specific SLI between the paralogs cytidine diphosphate diacylglycerol synthase 1 (CDS1) and CDS2. The essentiality of CDS2 for cell survival is observed for mesenchymal-like cancers, which have low or absent CDS1 expression and account for roughly half of all cancers. Mechanistica

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Aydın, Esranur, Ünal Metin Tokat, Eylül Özgü, et al. "Navigating uncharted territory: a case report and literature review on the remarkable response to personalized crizotinib containing combinational therapy in a pazopanib refractory patient with novel alterations." Therapeutic Advances in Medical Oncology 16 (January 2024). http://dx.doi.org/10.1177/17588359241247023.

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This paper presents a patient with a novel Ig-like-III domain fibroblast growth factor receptor (FGFR2) alteration (W290_P307>C) along with CDKN2A/B alterations and a cadherin 1 (CDH1) alteration. Initial responsiveness to pazopanib monotherapy was encouraging, yet progression occurred after 7.5 months. Following progression, the molecular tumor board recommended a combination therapy approach comprising pazopanib, crizotinib, and palbociclib to target all of the changed pathways at the same time. Pazopanib was chosen to specifically target the FGFR2 alteration, while crizotinib was selecte

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Klemm, Cinzia, Rowan S. M. Howell, and Peter H. Thorpe. "ScreenGarden: a shinyR application for fast and easy analysis of plate-based high-throughput screens." BMC Bioinformatics 23, no. 1 (2022). http://dx.doi.org/10.1186/s12859-022-04586-1.

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Abstract Background Colony growth on solid media is a simple and effective measure for high-throughput genomic experiments such as yeast two-hybrid, synthetic dosage lethality and Synthetic Physical Interaction screens. The development of robotic pinning tools has facilitated the experimental design of these assays, and different imaging software can be used to automatically measure colony sizes on plates. However, comparison to control plates and statistical data analysis is often laborious and pinning issues or plate specific growth effects can lead to the detection of false-positive growth

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Eisenstatt, Jessica R., Kentaro Ohkuni, Wei-Chun Au, et al. "Reduced gene dosage of histone H4 prevents CENP-A mislocalization and chromosomal instability in Saccharomyces cerevisiae." Genetics 218, no. 1 (2021). http://dx.doi.org/10.1093/genetics/iyab033.

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Abstract Mislocalization of the centromeric histone H3 variant (Cse4 in budding yeast, CID in flies, CENP-A in humans) to noncentromeric regions contributes to chromosomal instability (CIN) in yeast, fly, and human cells. Overexpression and mislocalization of CENP-A have been observed in cancers, however, the mechanisms that facilitate the mislocalization of overexpressed CENP-A have not been fully explored. Defects in proteolysis of overexpressed Cse4 (GALCSE4) lead to its mislocalization and synthetic dosage lethality (SDL) in mutants for E3 ubiquitin ligases (Psh1, Slx5, SCFMet30, and SCFCd

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Xi, Yao, Rui Xu, Shengnan Chen, et al. "TSG101 depletion dysregulates mitochondria and PML NBs, triggering MAD2-overexpressing interphase cell death (MOID) through AIFM1-PML-DAXX pathway." Cell Death & Disease 15, no. 11 (2024). http://dx.doi.org/10.1038/s41419-024-07229-w.

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AbstractOverexpression of mitotic arrest deficiency 2 (MAD2/MAD2L1), a pivotal component of the spindle assembly checkpoint (SAC), resulted in many types of cancer. Here we show that the depletion of tumor susceptibility gene 101 (TSG101), causes synthetic dosage lethality (SDL) in MAD2-overexpressing cells, and we term this cell death MAD2-overexpressing interphase cell death (MOID). The induction of MOID depends on PML and DAXX mediating mitochondrial AIFM1-release. MAD2, TSG101, and AIF-PML-DAXX axis regulate mitochondria, PML nuclear bodies (NBs), and autophagy with close inter-dependent p

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Kiyatkin, Eugene A., and Shinbe Choi. "Brain oxygen responses induced by opioids: focus on heroin, fentanyl, and their adulterants." Frontiers in Psychiatry 15 (January 17, 2024). http://dx.doi.org/10.3389/fpsyt.2024.1354722.

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Opioids are important tools for pain management, but abuse can result in serious health complications. Of these complications, respiratory depression that leads to brain hypoxia is the most dangerous, resulting in coma and death. Although all opioids at large doses induce brain hypoxia, danger is magnified with synthetic opioids such as fentanyl and structurally similar analogs. These drugs are highly potent, act rapidly, and are often not effectively treated by naloxone, the standard of care for opioid-induced respiratory depression. The goal of this review paper is to present and discuss bra

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Ennis, Elizabeth A., Paul Gresch, Anna L. Blobaum, Craig W. Lindsley, William T. Dauer, and Randy D. Blakely. "Do CHT Inhibitors Constitute a Possible Therapeutic Strategy for Dystonia? Studies with the Novel CHT Inhibitor ML352." FASEB Journal 30, S1 (2016). http://dx.doi.org/10.1096/fasebj.30.1_supplement.1272.12.

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Dystonias are a group of disorders characterized by abnormal involuntary contracting of musculature that causes twisting and turning of a patient's body. Though the etiology of each type of dystonia varies, many forms are treated with anticholinergic medications ranging from the use of botulinum toxin to muscarinic receptor antagonists. Although the efficacy of cholinergic treatments is limited by side effects, mechanistic evidence for cholinergic dysfunction along with efficacy of current cholinergic treatments encouraged us to pursue the development of inhibitors of the high affinity choline

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Y, Senthamaraikannan, Sundaram V, and Shanmugam R. "Bio-efficacy of Polyethylene Glycol-coated Selenium Nanocomposite Synthesised using Cocos nucifera Haustorium against HepG2 Cell Line." International Research Journal of Multidisciplinary Technovation, March 30, 2025, 165–83. https://doi.org/10.54392/irjmt25213.

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The selenium-based nanoparticles (SeNP) are prepared by the amalgamation of Cocos nucifera haustorium (CNH) with sodium selenite. Further conjugating the synthesised CNH-SeNP with polyethylene glycol (PEG) to design haustorium-based selenium nanocomposite (CNH-SeNC). The work involves characterising and studying their bio-potency. Maximum absorption in UV-visible spectrum was at 315 nm and 305 nm for CNH-SeNP and CNH-SeNC. FT-IR affirms the involvement of functional groups of haustorium in the fabrication of CHH-SeNP and CNH-SeNC. SEM result conveys the spherical structure of the CNH-SeNP and

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