2. Academic Validation
  3. The RPA-RNF20-SNF2H cascade promotes proper chromosome segregation and homologous recombination repair

The RPA-RNF20-SNF2H cascade promotes proper chromosome segregation and homologous recombination repair

  • Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2303479120. doi: 10.1073/pnas.2303479120.
Jimin Li 1,  Jingyu Zhao 1,  Xiaoli Gan 1,  Yanyan Wang 1,  Donghao Jiang 1,  Liang Chen 1,  Fangwei Wang 2,  Jingyan Xu 3,  Huadong Pei 4,  Jun Huang 2,  Xuefeng Chen 1
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Frontier Science Centre of Immunology and Metabolism, Wuhan University, Wuhan 430072, China.
  • 2 The Ministry of Education Key Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 3 Department of Hematology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210009, China.
  • 4 Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057.
PMID: 37155876 DOI: 10.1073/pnas.2303479120
Abstract

The human tumor suppressor Ring finger protein 20 (RNF20)-mediated histone H2B monoubiquitination (H2Bub) is essential for proper chromosome segregation and DNA repair. However, what is the precise function and mechanism of RNF20-H2Bub in chromosome segregation and how this pathway is activated to preserve genome stability remain unknown. Here, we show that the single-strand DNA-binding factor Replication protein A (RPA) interacts with RNF20 mainly in the S and G2/M phases and recruits RNF20 to mitotic centromeres in a centromeric R-loop-dependent manner. In parallel, RPA recruits RNF20 to chromosomal breaks upon DNA damage. Disruption of the RPA-RNF20 interaction or depletion of RNF20 increases mitotic lagging chromosomes and chromosome bridges and impairs BRCA1 and RAD51 loading and homologous recombination repair, leading to elevated chromosome breaks, genome instability, and sensitivities to DNA-damaging agents. Mechanistically, the RPA-RNF20 pathway promotes local H2Bub, H3K4 dimethylation, and subsequent SNF2H recruitment, ensuring proper Aurora B kinase activation at centromeres and efficient loading of repair proteins at DNA breaks. Thus, the RPA-RNF20-SNF2H cascade plays a broad role in preserving genome stability by coupling H2Bub to chromosome segregation and DNA repair.

Keywords

H2B ubiquitination; RNF20; RPA; chromosome segregation; homologous recombination.

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