气候变化领域集成服务门户(CCPortal): DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress

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DOI	10.1073/PNAS.2008821117
	DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress
	Wang R.; Lenoir W.F.; Wang C.; Su D.; McLaughlin M.; Hu Q.; Shen X.; Tian Y.; Klages-Mundt N.; Lynn E.; Wood R.D.; Chen J.; Hart T.; Li L.
发表日期	2021
ISSN	00278424
起始页码	33436
结束页码	33445
卷号	117 期号:52
英文摘要	Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4. As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	DNA polymerase; Fanconi anemia pathway; Lesion bypass; Whole genome fitness screens
语种	英语
scopus关键词	cyclin dependent kinase 4; DNA directed DNA polymerase; DNA polymerase iota; CRISPR Cas system; DNA damage; DNA replication; enzymology; Fanconi anemia; genetics; HCT 116 cell line; human; human genome; lethal mutation; metabolism; mutation; physiological stress; CRISPR-Cas Systems; Cyclin-Dependent Kinase 4; DNA Damage; DNA Replication; DNA-Directed DNA Polymerase; Fanconi Anemia; Genome, Human; HCT116 Cells; Humans; Mutation; Stress, Physiological; Synthetic Lethal Mutations
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179681
作者单位	Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States; University of Texas MD Anderson Cancer Center, University of Texas Health Science Center at, Houston Graduate School of Biomedical Sciences, Houston, TX 77030, United States; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States; Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
推荐引用方式 GB/T 7714	Wang R.,Lenoir W.F.,Wang C.,et al. DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress[J],2021,117(52).
APA	Wang R..,Lenoir W.F..,Wang C..,Su D..,McLaughlin M..,...&Li L..(2021).DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Wang R.,et al."DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).