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Baranes-Bachar, Keren,Levy-Barda, Adva,Oehler, Judith,Reid, Dylan A.,Soria-Bretones, Isabel,Voss, Ty C.,Chung, Dudley,Park, Yoon,Liu, Chao,Yoon, Jong-Bok,Li, Wei,Dellaire, Graham,Misteli, Tom,Huertas, Elsevier 2018 Molecular cell Vol.69 No.5
<P><B>Summary</B></P> <P>Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The E3/E4 ubiquitin ligase UBE4A is a new player in the DNA damage response </LI> <LI> UBE4A is required for optimal repair of DNA double-strand breaks </LI> <LI> After initial action of E3 ubiquitin ligases, UBE4A modulates ubiquitylation extent </LI> <LI> UBE4A’s activity is required for appropriate balance of repair pathways </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>