气候变化领域集成服务门户(CCPortal): Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions

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DOI	10.1073/pnas.2100240118
	Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions
	Hamza A.; Amitzi L.; Ma L.; Driessen M.R.M.; O'Neil N.J.; Hieter P.
发表日期	2021
ISSN	00278424
卷号	118 期号:14
英文摘要	Genetic screens can identify synthetic lethal (SL) interactions and uncover potential anticancer therapeutic targets. However, most SL screens have utilized knockout or knockdown approaches that do not accurately mimic chemical inhibition of a target protein. Here, we test whether missense mutations can be utilized as a model for a type of protein inhibition that creates a dominant gain-of-function cytotoxicity. We expressed missense mutations in the FEN1 endonuclease and the replication-associated helicase, CHL1, that inhibited enzymatic activity but retained substrate binding, and found that these mutations elicited a dominant SL phenotype consistent with the generation of cytotoxic protein-DNA or protein-protein intermediates. Genetic screens with nuclease-defective hFEN1 and helicase-deficient yCHL1 captured dominant SL interactions, in which ectopic expression of the mutant form, in the presence of the wild-type form, caused SL in specific mutant backgrounds. Expression of nuclease-defective hFEN1 in yeast elicited DNA binding-dependent dominant SL with homologous recombination mutants. In contrast, dominant SL interactions with helicase-deficient yCHL1 were observed in spindleassociated, Ctf18-alternative replication factor C (Ctf18-RFC) clamp loader complex, and cohesin mutant backgrounds. These results highlight the different mechanisms underlying SL interactions that occur in the presence of an inhibited form of the target protein and point to the utility of modeling trapping mutations in pursuit of more clinically relevant SL interactions. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Chl1 helicasè; DNA trapping`; Dominant missense mutations; Dominant synthetic lethalitỳ; Fen1 endonucleasè
语种	英语
scopus关键词	cohesin; endonuclease; helicase; Article; CHL1 gene; controlled study; cytotoxicity; DNA binding; DNA damage; enzyme activity; enzyme inhibition; enzyme substrate complex; FEN1 gene; gain of function mutation; gene expression; gene function; gene identification; gene interaction; gene replication; genetic screening; homologous recombination; human; lethal mutation; missense mutation; phenotype; priority journal; protein DNA binding; protein function; protein protein interaction; protein targeting; replisome; Western blotting
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/180015
作者单位	Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
推荐引用方式 GB/T 7714	Hamza A.,Amitzi L.,Ma L.,et al. Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions[J],2021,118(14).
APA	Hamza A.,Amitzi L.,Ma L.,Driessen M.R.M.,O'Neil N.J.,&Hieter P..(2021).Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions.Proceedings of the National Academy of Sciences of the United States of America,118(14).
MLA	Hamza A.,et al."Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions".Proceedings of the National Academy of Sciences of the United States of America 118.14(2021).