SCIENCE CHINA Life Sciences Journal Cover Design Service (H3K36)

SCIENCE CHINA Life Sciences

29 Feb 2024

Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair

Runfa Chen^1,†, Meng-Jie Zhao^1,†, Yu-Min Li¹, Ao-Hui Liu¹, Ru-Xin Wang¹, Yu-Chao Mei¹, Xuefeng Chen², Hai-Ning Du^1,*

10.1007/s11427-024-2543-9

Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.