BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation.
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BRCA1 单倍体不足被 RNF168 介导的染色质泛素化掩盖。
DOI：
10.1016/j.molcel.2018.12.010
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发表时间：
2019
期刊：
影响因子：
16
通讯作者：
Nusse
中科院分区：
文献类型：
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作者：
Zong,Dali;Adam,Salomé;Wang,Yifan;Sasanuma,Hiroyuki;Callén,Elsa;Murga,Matilde;Day,Amanda;Kruhlak,MichaelJ;Wong,Nancy;Munro,Meagan;RayChaudhuri,Arnab;Karim,Baktiar;Xia,Bing;Takeda,Shunichi;Johnson,Neil;Durocher,Daniel;Nusse
BRCA 1在同源重组（HR）过程中的两个不同步骤发挥作用。最初，它促进DNA末端切除，随后它招募PALB 2和BRCA 2介体复合物，其稳定RAD 51-DNA核蛋白丝。53 BP 1的缺失通过增加切除来挽救BRCA 1缺陷细胞中的HR缺陷，这表明当53 BP 1缺失时，BRCA 1在RAD 51加载中的下游作用是无效的。在这里，我们表明，E3泛素连接酶RNF 168，除了其典型的作用，在抑制末端切除，以冗余的方式与BRCA 1加载PALB 2到受损的DNA。RNF 168的缺失否定了通过53 BP 1缺失对BRCA 1缺陷的合成性拯救，并且它使BRCA 1杂合子小鼠容易患癌症。BRCA 1 +/− RNF 168 −/−细胞缺乏RAD 51灶，并且对PARP抑制剂高度敏感，而强制靶向PALB 2突变细胞中的DNA断裂则规避了BRCA 1单倍不足。因此，抑制染色质泛素途径可能是BRCA 1缺陷型癌症的一种合成致死策略。
BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 mediator complex, which stabilizes RAD51-DNA nucleoprotein filaments. Loss of 53BP1 rescues the HR defect in BRCA1-deficient cells by increasing resection, suggesting that BRCA1's downstream role in RAD51 loading is dispensable when 53BP1 is absent. Here we show that the E3 ubiquitin ligase RNF168, in addition to its canonical role in inhibiting end resection, acts in a redundant manner with BRCA1 to load PALB2 onto damaged DNA. Loss of RNF168 negates the synthetic rescue ofBRCA1deficiency by53BP1deletion, and it predisposesBRCA1heterozygous mice to cancer.BRCA1+/−RNF168−/−cells lack RAD51 foci and are hypersensitive to PARP inhibitor, whereas forced targeting of PALB2 to DNA breaks in mutant cells circumventsBRCA1haploinsufficiency. Inhibiting the chromatin ubiquitin pathway may, therefore, be a synthetic lethality strategy forBRCA1-deficient cancers.