Chfr and RNF8 synergistically regulate ATM activation

Protein ubiquitination is a critical component of the DNA damage response. To study the mechanism of the DNA damage-induced ubiquitination pathway, we analyzed the impact of the loss of two E3 ubiquitin ligases, RNF8 and Chfr. Interestingly, DNA damage-induced ATM activation is suppressed in RNF8 and Chfr double-deficient (DKO) cells, and DKO mice develop thymic lymphomas that are nearly diploid but harbor clonal chromosome translocations. Moreover, DKO mice and cells are hypersensitive to ionizing radiation. We show evidence that RNF8 and Chfr synergistically regulate histone ubiquitination to control histone H4K16 acetylation through MRG15-dependent acetyltransferase complexes. Through these complexes, RNF8 and CHFR affect chromatin relaxation and modulate ATM activation and DNA damage response pathways. Collectively, our findings demonstrate that two chromatin remodeling factors, RNF8 and Chfr, function together to activate ATM and maintain genomic stability in vivo.