The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress
The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress
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DOI：
10.1038/nature08593
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发表时间：
2009-12-17
期刊：
影响因子：
64.8
通讯作者：
Solomon, Ellen
中科院分区：
文献类型：
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作者：
Morris, Joanna R.;Boutell, Chris;Solomon, Ellen
BRCA1基因突变与乳腺癌和卵巢癌的高风险相关。BRCA1参与DNA损伤反应，发挥泛素连接酶的作用。然而，人们对其监管仍知之甚少。在这里，我们报道了BRCA1被小泛素样修饰物(SUMO)修饰以响应遗传毒性应激，并与SUMO1、SUMO2/3和SUMO结合酶Ubc9共同定位于DNA损伤部位。PIAS相扑E3连接酶与BRCA1共定位并调节相扑修饰，是细胞中BRCA1泛素连接酶活性所必需的。在体外，BRCA1/BARD1异源二聚体的SUMO修饰大大提高了它的连接酶活性，证明它是一种SUMO调节的泛素连接酶(SRUbL)。此外，PIAS相扑连接酶对于RNF8后双链DNA(DsDNA)损伤修复蛋白的完全积累以及熟练的双链断裂修复都是必需的。这些数据表明，SUMO化途径在哺乳动物DNA损伤反应中起着重要作用。
Mutations in BRCA1 are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase. However, its regulation remains poorly understood. Here we report that BRCA1 is modified by small ubiquitin-like modifier ( SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO-conjugating enzyme Ubc9. PIAS SUMO E3 ligases co-localize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro SUMO modification of the BRCA1/BARD1 heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase (SRUbL). Further, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.