PARylated PDHE1a generates acetyl-CoA for local chromatin acetylation and DNA damage repair

Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in acetylation status, but how the large demands of acetyl-CoA are met is unclear. Here, we report that pyruvate dehydrogenase 1 & alpha; (PDHE1 & alpha;) catalyzes pyruvate metabolism to rapidly provide acetyl-CoA in response to DNA damage. We show that PDHE1 & alpha; is quickly recruited to chromatin in a polyADP-ribosylation-dependent manner, which drives acetyl-CoA generation to support local chromatin acetylation around DSBs. This process increases the formation of relaxed chromatin to facilitate repair-factor loading, genome stability and cancer cell resistance to DNA-damaging treatments in vitro and in vivo. Indeed, we demonstrate that blocking polyADP-ribosylation-based PDHE1 & alpha; chromatin recruitment attenuates chromatin relaxation and DSB repair efficiency, resulting in genome instability and restored radiosensitivity. These findings support a mechanism in which chromatin-associated PDHE1 & alpha; locally generates acetyl-CoA to remodel the chromatin environment adjacent to DSBs and promote their repair. Here, the authors show that PDHE1 & alpha; accumulates at DNA double-strand breaks, in a PARylation-dependent manner, where it locally supplies acetyl-CoA for histone acetylation. These events facilitate remodeling of the chromatin landscape and efficient repair.

Automated summary

In response to DNA damage, pyruvate dehydrogenase 1 & alpha; (PDHE1 & alpha;) rapidly generates acetyl-CoA by catalyzing pyruvate metabolism, which is necessary for chromatin relaxation and histone acetylation around double-strand breaks (DSBs). PDHE1 & alpha; is recruited to chromatin in a polyADP-ribosylation-dependent manner and enhances DSB repair efficiency, genome stability, and cancer cell resistance to DNA-damaging treatments in vitro and in vivo.