ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair.
ZMYM3 regulates BRCA1 localization at damaged chromatin to promote DNA repair.
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DOI：
10.1101/gad.292516.116
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发表时间：
2017-02-01
影响因子：
10.5
通讯作者：
Miller KM
中科院分区：
文献类型：
--
作者：
Leung JW;Makharashvili N;Agarwal P;Chiu LY;Pourpre R;Cammarata MB;Cannon JR;Sherker A;Durocher D;Brodbelt JS;Paull TT;Miller KM
在这项研究中，Leung等人鉴定了ZMYM 3（锌指、骨髓增生和智力迟钝3型）作为一种染色质相互作用蛋白，通过同源重组促进DNA修复。这项工作确定了一个关键的染色质结合DNA损伤反应因子，ZMYM 3，它调节BRCA 1染色质内的功能，以确保维持基因组的完整性。染色质将DNA损伤反应因子连接到受损DNA的位点，以促进DNA损伤的信号传导和修复。组蛋白H2 A变体H2 AX、H2 AZ和macroH 2A代表促进DNA修复的关键染色质成分。通过对这些变体的蛋白质组学筛选，我们将ZMYM 3（锌指、骨髓增生和智力迟钝3型）鉴定为通过同源重组（HR）促进DNA修复的染色质相互作用蛋白。ZMYM 3通过与核小体的组蛋白和DNA组分的二价相互作用被募集到DNA双链断裂。我们发现，ZMYM 3通过与BRCA 1-A亚复合物的组分（包括ABRA 1和RAP 80）的特异性相互作用，将HR因子BRCA 1与受损的染色质联系起来。通过调节ABRA 1向受损染色质的募集，ZMYM 3促进BRCA 1与DNA损伤位点和染色质相互作用的微调。与调节BRCA 1功能的作用一致，ZMYM 3缺陷导致HR修复受损和基因组不稳定性。因此，我们的工作确定了一个关键的染色质结合DNA损伤反应因子，ZMYM 3，它调节BRCA 1染色质内的功能，以确保维持基因组的完整性。
In this study, Leung et al. identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination. This work identifies a critical chromatin-binding DNA damage response factor, ZMYM3, which modulates BRCA1 functions within chromatin to ensure the maintenance of genome integrity. Chromatin connects DNA damage response factors to sites of damaged DNA to promote the signaling and repair of DNA lesions. The histone H2A variants H2AX, H2AZ, and macroH2A represent key chromatin constituents that facilitate DNA repair. Through proteomic screening of these variants, we identified ZMYM3 (zinc finger, myeloproliferative, and mental retardation-type 3) as a chromatin-interacting protein that promotes DNA repair by homologous recombination (HR). ZMYM3 is recruited to DNA double-strand breaks through bivalent interactions with both histone and DNA components of the nucleosome. We show that ZMYM3 links the HR factor BRCA1 to damaged chromatin through specific interactions with components of the BRCA1-A subcomplex, including ABRA1 and RAP80. By regulating ABRA1 recruitment to damaged chromatin, ZMYM3 facilitates the fine-tuning of BRCA1 interactions with DNA damage sites and chromatin. Consistent with a role in regulating BRCA1 function, ZMYM3 deficiency results in impaired HR repair and genome instability. Thus, our work identifies a critical chromatin-binding DNA damage response factor, ZMYM3, which modulates BRCA1 functions within chromatin to ensure the maintenance of genome integrity.