Interaction of BARD1 and HP1 Is Required for BRCA1 Retention at Sites of DNA Damage.
Interaction of BARD1 and HP1 Is Required for BRCA1 Retention at Sites of DNA Damage.
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DOI：
10.1158/0008-5472.can-14-2796
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发表时间：
2015-04-01
期刊：
影响因子：
11.2
通讯作者：
Ohta T
中科院分区：
文献类型：
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作者：
Wu W;Nishikawa H;Fukuda T;Vittal V;Asano M;Miyoshi Y;Klevit RE;Ohta T
BRCA1/BARD1复合物在DNA损伤位点的稳定保留是对DNA双链断裂（DSB）的适当反应所必需的。在这里，我们证明了BARD 1的BRCT结构域通过与HP 1的相互作用对其保留至关重要。在DNA损伤的反应中，BARD 1以ATM依赖性但不依赖于RNF168的方式与Lys9-二甲基化组蛋白H3（H3K9me2）相互作用。这种相互作用主要由HP 1 γ介导。BARD 1 BRCT结构域中保守的HP1结合基序在体外直接与HP1的chromoshadow结构域相互作用。该基序中的突变（或所有三种HP 1亚型的同时耗尽）破坏了BARD 1、BRCA 1和CtIP在DSB位点的保留，并允许RIF 1（非同源末端连接的效应子）在S期受损位点异位积累。UNC0638是一种组蛋白赖氨酸甲基转移酶（HKMT）的小分子抑制剂，可消除滞留，并与聚（ADP-核糖）聚合酶抑制剂olaparib协同作用，阻断癌细胞生长。总之，我们的研究结果显示了BARD 1如何促进BRCA 1/BARD 1复合物在受损DNA位点的保留，并建议使用HKMT抑制剂来利用PARP抑制剂治疗乳腺癌。
Stable retention of BRCA1/BARD1 complexes at sites of DNA damage is required for the proper response to DNA double-strand breaks (DSB). Here, we demonstrate that the BRCT domain of BARD1 is crucial for its retention through interaction with HP1. In response to DNA damage, BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) in an ATM-dependent but RNF168-independent manner. This interaction is mediated primarily by HP1γ. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacted with the chromoshadow domain of HP1 in vitro. Mutations in this motif (or simultaneous depletion of all three HP1 isoforms) disrupted retention of BARD1, BRCA1 and CtIP at DSB sites and allowed ectopic accumulation of RIF1, an effector of non-homologous end joining, at damaged loci in S phase. UNC0638, a small molecule inhibitor of histone lysine methyltransferase (HKMT), abolished retention and cooperated with the poly(ADP-ribose) polymerase inhibitor olaparib to block cancer cell growth. Taken together, our findings show how BARD1 promotes retention of the BRCA1/BARD1 complex at damaged DNA sites, and suggest the use of HKMT inhibitors to leverage the application of PARP inhibitors to treat breast cancer.