2. Academic Validation
  3. GAPDH facilitates homologous recombination repair by stabilizing RAD51 in an HDAC1-dependent manner

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

  • EMBO Rep. 2023 Jun 12;e56437. doi: 10.15252/embr.202256437.
Munan Shi 1,  Jiajia Hou 1,  Weichu Liang 1,  Qianwen Li 2,  Shan Shao 1,  Shusheng Ci 1 3,  Chuanjun Shu 4,  Xingqi Zhao 1,  Shanmeizi Zhao 1,  Miaoling Huang 1,  Congye Wu 5,  Zhigang Hu 1,  Lingfeng He 1,  Zhigang Guo 1,  Feiyan Pan 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
  • 2 Department of Radiotherapy, Taikang Xianlin Drum Tower Hospital, Nanjing University, Nanjing, China.
  • 3 School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
  • 4 Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China.
  • 5 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
PMID: 37306047 DOI: 10.15252/embr.202256437
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.

Keywords

GAPDH; HDAC1; RAD51; homologous recombination; protein stability.

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