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

Jimin Li, Jingyu Zhao, Xiaoli Gan, Yanyan Wang, Donghao Jiang, Liang Chen, Fangwei Wang, Jingyan Xu, Huadong Pei, Jun Huang, Xuefeng Chen

Proceedings of the National Academy of Sciences of the United States of America 2023 May 16

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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.

Citation

Jimin Li, Jingyu Zhao, Xiaoli Gan, Yanyan Wang, Donghao Jiang, Liang Chen, Fangwei Wang, Jingyan Xu, Huadong Pei, Jun Huang, Xuefeng Chen. The RPA-RNF20-SNF2H cascade promotes proper chromosome segregation and homologous recombination repair. Proceedings of the National Academy of Sciences of the United States of America. 2023 May 16;120(20):e2303479120