Requirement of WDR70 for POLE3-mediated DNA double-strand breaks repair

H2BK120ub1 triggers several prominent downstream histone modification pathways and changes in chromatin structure, therefore involving it into multiple critical cellular processes including DNA transcription and DNA damage repair. Although it has been reported that H2BK120ub1 is mediated by RNF20/40 and CRL4(WDR70), less is known about the underlying regulation mechanism for H2BK120ub1 by WDR70. By using a series of biochemical and cell-based studies, we find that WDR70 promotes H2BK120ub1 by interacting with RNF20/40 complex, and deposition of H2BK120ub1 and H3K79me2 in POLE3 loci is highly sensitive to POLE3 transcription. Moreover, we demonstrate that POLE3 interacts CHRAC1 to promote DNA repair by regulation on the expression of homology-directed repair proteins and KU80 recruitment and identify CHRAC1 D121Y mutation in colorectal cancer, which leads to the defect in DNA repair due to attenuated the interaction with POLE3. These findings highlight a previously unknown role for WDR70 in maintenance of genomic stability and imply POLE3 and CHRAC1 as potential therapeutic targets in cancer.