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PARP1 依赖性募集 FBXL10-RNF68-RNF2 泛素连接酶至 DNA 损伤部位控制 H2A.Z 的加载。

PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading.

机构信息

Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.

Perlmutter Cancer Center, New York University School of Medicine, New York, United States.

出版信息

Elife. 2018 Jul 9;7:e38771. doi: 10.7554/eLife.38771.

DOI:10.7554/eLife.38771
PMID:29985131
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6037479/
Abstract

The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono-ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono-ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR.

摘要

哺乳动物 FBXL10-RNF68-RNF2 泛素连接酶复合物（FRRUC）单泛素化 H2A 在 Lys119 以抑制未应激细胞中的转录。我们发现，FRRUC 以依赖 PARP1 和 TIMLESS 的方式快速且短暂地募集到 DNA 损伤部位，以促进 H2A 在 Lys119 的单泛素化、H2A 水平的局部降低以及 H2A.Z 的掺入。FRRUC 和 H2A.Z 均促进转录抑制、双链断裂信号转导和同源重组修复（HRR）。所有这些事件都需要 FRRUC 的存在和活性。此外，FRRUC 及其活性对于 BMI1-RNF2 和 MEL18-RNF2 的适当募集是必需的，这两种其他泛素连接酶在基因毒性应激下单泛素化 H2A 的 Lys119。值得注意的是，尽管 H2A.Z 不是 H2A 单泛素化所必需的，但后者的损害会抑制 H2A.Z 的掺入。我们提出，FRRUC 的募集代表了 HRR 的早期和关键调节步骤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9ac8/6037479/304de720649f/elife-38771-resp-fig2.jpg
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