RAD18 directs DNA double-strand break repair by homologous recombination to post-replicative chromatin

被引:4
|
作者
Palek, Matous [1 ,2 ]
Palkova, Natalie [1 ,2 ]
Kleiblova, Petra [3 ,4 ]
Kleibl, Zdenek [3 ,4 ]
Macurek, Libor [1 ]
机构
[1] Czech Acad Sci, Canc Cell Biol, Inst Mol Genet, CZ-14220 Prague, Czech Republic
[2] Charles Univ Prague, Dept Cell Biol, Fac Sci, Prague, Czech Republic
[3] Charles Univ Prague, Inst Med Biochem & Lab Diagnost, Fac Med 1, Prague, Czech Republic
[4] Gen Univ Hosp Prague, Prague, Czech Republic
关键词
SMC5/6; COMPLEX; FUNCTIONAL-CHARACTERIZATION; DAMAGE RESPONSE; UBIQUITIN; 53BP1; RECOGNITION; RECRUITMENT; MECHANISMS; VIABILITY; RESECTION;
D O I
10.1093/nar/gkae499
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
RAD18 is an E3 ubiquitin ligase that prevents replication fork collapse by promoting DNA translesion synthesis and template switching. Besides this classical role, RAD18 has been implicated in homologous recombination; however, this function is incompletely understood. Here, we show that RAD18 is recruited to DNA lesions by monoubiquitination of histone H2A at K15 and counteracts accumulation of 53BP1. Super-resolution microscopy revealed that RAD18 localizes to the proximity of DNA double strand breaks and limits the distribution of 53BP1 to the peripheral chromatin nanodomains. Whereas auto-ubiquitination of RAD18 mediated by RAD6 inhibits its recruitment to DNA breaks, interaction with SLF1 promotes RAD18 accumulation at DNA breaks in the post-replicative chromatin by recognition of histone H4K20me0. Surprisingly, suppression of 53BP1 function by RAD18 is not involved in homologous recombination and rather leads to reduction of non-homologous end joining. Instead, we provide evidence that RAD18 promotes HR repair by recruiting the SMC5/6 complex to DNA breaks. Finally, we identified several new loss-of-function mutations in RAD18 in cancer patients suggesting that RAD18 could be involved in cancer development. Graphical Abstract
引用
收藏
页码:7687 / 7703
页数:17
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