PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair.
PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair.
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DOI：
10.1158/2159-8290.cd-13-0891
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发表时间：
2014-12
期刊：
影响因子：
28.2
通讯作者：
Livingston DM
中科院分区：
文献类型：
--
作者：
Hu Y;Petit SA;Ficarro SB;Toomire KJ;Xie A;Lim E;Cao SA;Park E;Eck MJ;Scully R;Brown M;Marto JA;Livingston DM
BRCA1促进同源重组介导的DNA修复(HRR)。然而，HRR必须受到严格监管，以防止非法重组。我们先前发现BRCA1的HRR功能受RAP80复合体的调控，但其机制尚不清楚。我们现在已经观察到PARP1与多-ADP-核糖酸盐(又名。宾夕法尼亚州)BRCA1。旁合作用针对BRCA1的DNA结合域，下调其功能。此外，RAP80还含有一个多聚ADP-核糖(PAR)相互作用结构域，它能与PAR化的BRCA1结合，有助于维持PARP1-BRCA1-RAP80复合体的稳定性。BRCA1蛋白合成是BRCA1 HRR控制的关键步骤。当BRCA1部分合成缺陷时，会引起过度的HRR和基因组不稳定的表现。在散发性乳腺癌细胞系和患者来源的肿瘤异种移植(PDX)模型中，BRCA1 PARsys和/或RAP80的表达存在缺陷。这些观察结果与这样一种可能性是一致的，即这种缺陷在慢性时，会导致BRCA1+/+个体的肿瘤发展。
BRCA1 promotes homologous recombination-mediated DNA repair (HRR). However, HRR must be tightly regulated to prevent illegitimate recombination. We previously found that BRCA1 HRR function is regulated by the RAP80 complex, but the mechanism was unclear. We have now observed that PARP1 interacts with and poly-ADP-ribosylates (aka. PARsylates) BRCA1. PARsylation is directed at the BRCA1 DNA binding domain and down-modulates its function. Moreover, RAP80 contains a poly-ADP-ribose (PAR) interacting domain that binds PARsylated BRCA1 and helps to maintain the stability of PARP1-BRCA1-RAP80 complexes. BRCA1 PARsylation is a key step in BRCA1 HRR control. When BRCA1 PARsylation is defective, it gives rise to excessive HRR and manifestations of genome instability. BRCA1 PARsylation and/or RAP80 expression is defective in a subset of sporadic breast cancer cell lines and patient-derived tumor xenograft (PDX) models. These observations are consistent with the possibility that such defects, when chronic, contribute to tumor development in BRCA1+/+ individuals.