GAPDH facilitates homologous recombination repair by stabilizing RAD51 in an HDAC1-dependent manner.

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2023-08-03 Epub Date: 2023-06-12 DOI:10.15252/embr.202256437

Munan Shi, Jiajia Hou, Weichu Liang, Qianwen Li, Shan Shao, Shusheng Ci, Chuanjun Shu, Xingqi Zhao, Shanmeizi Zhao, Miaoling Huang, Congye Wu, Zhigang Hu, Lingfeng He, Zhigang Guo, Feiyan Pan

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引用次数: 0

Abstract

Homologous recombination (HR), a form of error-free DNA double-strand break (DSB) repair, is important for the maintenance of genomic integrity. Here, we identify a moonlighting protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as a regulator of HR repair, which is mediated through HDAC1-dependent regulation of RAD51 stability. Mechanistically, in response to DSBs, Src signaling is activated and mediates GAPDH nuclear translocation. Then, GAPDH directly binds with HDAC1, releasing it from its suppressor. Subsequently, activated HDAC1 deacetylates RAD51 and prevents it from undergoing proteasomal degradation. GAPDH knockdown decreases RAD51 protein levels and inhibits HR, which is re-established by overexpression of HDAC1 but not SIRT1. Notably, K40 is an important acetylation site of RAD51, which facilitates stability maintenance. Collectively, our findings provide new insights into the importance of GAPDH in HR repair, in addition to its glycolytic activity, and they show that GAPDH stabilizes RAD51 by interacting with HDAC1 and promoting HDAC1 deacetylation of RAD51.

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GAPDH 以依赖 HDAC1 的方式稳定 RAD51，从而促进同源重组修复。

同源重组（HR）是无差错 DNA 双链断裂（DSB）修复的一种形式，对维护基因组完整性非常重要。在这里，我们发现了一种月光蛋白--甘油醛-3-磷酸脱氢酶（GAPDH）--是 HR 修复的调节因子，它通过 HDAC1 依赖性调节 RAD51 的稳定性来介导 HR 修复。从机制上讲，DSB发生时，Src信号被激活并介导GAPDH核转位。然后，GAPDH 直接与 HDAC1 结合，将其从抑制因子中释放出来。随后，活化的 HDAC1 会对 RAD51 进行去乙酰化，阻止其进行蛋白酶体降解。敲除 GAPDH 会降低 RAD51 蛋白水平并抑制 HR，而过量表达 HDAC1 而不是 SIRT1 则会重新抑制 HR。值得注意的是，K40是RAD51的一个重要乙酰化位点，有助于维持其稳定性。总之，我们的研究结果为了解 GAPDH 在 HR 修复中的重要性以及其糖酵解活性提供了新的见解，研究结果表明 GAPDH 通过与 HDAC1 相互作用并促进 HDAC1 对 RAD51 的去乙酰化来稳定 RAD51。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.