RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage.
RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage.
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DOI：
10.1038/s41467-021-25346-4
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发表时间：
2021-08-18
影响因子：
16.6
通讯作者：
Johnson N
中科院分区：
文献类型：
--
作者：
Krais JJ;Wang Y;Patel P;Basu J;Bernhardy AJ;Johnson N
DNA损伤会导致染色质发生各种各样的变化。RNF168 E3泛素连接酶在赖氨酸(K)13/15 （mUb-H2A）处催化组蛋白H2A的单泛素化，形成DNA修复蛋白的结合模块。BRCA1促进同源重组（HR），部分是通过其与PALB2的相互作用，以及形成更大的BRCA1-PALB2- brca2 - rad51 （BRCA1- p）复合体。BRCA1-P被招募到DNA断裂周围染色质的机制尚不清楚。在这项研究中，我们揭示了rnf168调控的信号通路负责将BRCA1-P复合物定位到DNA损伤。利用携带Brca1CC（卷曲线圈）突变阻断Brca1-Palb2相互作用的小鼠，我们发现了Rnf168−和Brca1CC等位基因之间的epistatic关系，这种关系破坏了发育，降低了Palb2-Rad51的定位效率。在机制上，我们发现rnf168产生的mUb-H2A通过BRCT结构域泛素依赖性招募基序（BUDR）招募BARD1。随后，BARD1-BRCA1通过CC结构域介导的BRCA1-PALB2相互作用在DNA断裂处积累PALB2-RAD51。总之，这些发现建立了一系列连接DNA损伤信号和HR修复机制的分子相互作用。众所周知，BRCA1-PALB2-BRCA2-RAD51 （BRCA1-P）复合体在DNA修复中起着重要作用，但如何调节复合体的招募仍然是一个有趣的问题。本文作者揭示了同源重组修复过程中通过BARD1-BRCA1介导PALB2募集的RNF168活性的机制。
DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168− and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery. The BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex is well known to play a fundamental role in DNA repair, but how the complex recruitment is regulated is still a matter of interest. Here the authors reveal mechanistic insights into RNF168 activity being responsible for PALB2 recruitment, through BARD1-BRCA1 during homologous recombination repair.
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影响因子：
16.6
作者：
Soo Lee N;Jin Chung H;Kim HJ;Yun Lee S;Ji JH;Seo Y;Hun Han S;Choi M;Yun M;Lee SG;Myung K;Kim Y;Chul Kang H;Kim H
通讯作者：
Kim H
影响因子：
8.8
作者：
Cruz-Garcia, Andres;Lopez-Saavedra, Ana;Huertas, Pablo
通讯作者：
Huertas, Pablo
DOI：
10.1038/nrm2831
发表时间：
2010-02
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Munoz, Meilen C.;Laulier, Corentin;Stark, Jeremy M.
通讯作者：
Stark, Jeremy M.
影响因子：
8.8
作者：
Nacson, Joseph;Krais, John J.;Johnson, Neil
通讯作者：
Johnson, Neil