PARylated PDHE1a generates acetyl-CoA for local chromatin acetylation and DNA damage repair
Chromatin relaxation is a prerequisite step for allowing DNA repair machinery to access double-strand breaks (DSBs), and local histones around the DNA breaks suffer from prompt acetylation changes. However, an intriguing question remains as to where the quick and robust acetyl-CoA is produced. Here, we report that pyruvate dehydrogenase 1a (PDHE1a) catalyzes pyruvate metabolic processes and provides acetyl-CoA promptly in response to DNA damage. PDHE1a was quickly recruited to chromatin in a PARylation-dependent manner, which further drove the local acetyl-CoA generation to support local chromatin acetylation around the DSB regions. In turn, this process increased the formation of relaxed chromatin to benefit repair factor loading, thus promote DSB repair to ultimately maintain genome stability and contribute to the resistance of cancer cells to DNA-damaging treatments in vitro and in vivo. Consistent with this, blocking PARylation-based PDHE1a chromatin recruitment markedly attenuated chromatin relaxation and the DSB repair efficiency, and resulted in genome instability and radio re-sensitivity. Collectively, these findings identified an undescribed mechanism that underlies site-directed acetyl-CoA generation involving chromatin-associated PDHE1a and its instrumental function in DNA repair and regulating local chromatin acetylation around DSB sites. The findings provide potential routes to disrupt a key mechanism of cancer cell resistance to genotoxic damage. Overall design: Examination of pan-Lysine acetylation signal distribution upon DNA damage.