Matches in SemOpenAlex for { <https://semopenalex.org/work/W3126675804> ?p ?o ?g. }
- W3126675804 abstract "Significance Schlafen-11 (SLFN11) inactivation leads to chemoresistance of a broad range of DNA-damaging agents. We uncover an expanded Ataxia Telangiectasia- and Rad3-related (ATR)-mediated signaling network that overcomes chemoresistance by an unbiased genome-wide RNAi screen in SLFN11 -knockout cells and is validated with clinically developing ATR/CHK1 inhibitors. ATR inhibition induces CDT1 phosphorylation, leading to mitotic catastrophe cell death in SLFN11-deficient cells. We identify a key role of SLFN11 for CDT1 degradation by binding to DDB1–CUL4 CDT2 ubiquitin ligase during DNA damage, thereby blocking replication reactivation by which SLFN11-deficient cells cause chemoresistance. Our findings provide a rationale for combination therapy with ATR inhibitor and DNA-targeted drugs, and reveal how SLFN11 irreversibly arrests replication during DNA damage acting as a cofactor of CUL4 CDT2 ubiquitin ligase." @default.
- W3126675804 created "2021-02-15" @default.
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- W3126675804 date "2021-02-03" @default.
- W3126675804 modified "2023-10-11" @default.
- W3126675804 title "SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors" @default.
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- W3126675804 doi "https://doi.org/10.1073/pnas.2015654118" @default.
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