KAT5-mediated acetylation of PC4 facilitates DNA repair by promoting chromatin reorganization

Abstract

Human positive coactivator 4 (PC4) is a highly abundant non-histone chromatin protein involved in diverse cellular processes, including transcription regulation, genome organization, autophagy, B-cell differentiation, neurogenesis, DNA repair, etc. Most PC4 is phosphorylated in cells, which interacts with core histones and the linker histone H1 to confer the compact heterochromatin state of the genome. Knocking down PC4 at both cellular and organismal levels leads to significant chromatin decondensation, altered epigenetic landscape, enhanced autophagy, and increased DNA damage susceptibility. Here, we report that besides p300, PC4 also gets acetylated by DNA repair, facilitating lysine acetyltransferase KAT5 (Tip60) at a specific lysine residue (PC4K80) when the cells are subjected to DNA damage. The vulnerability of DNA in PC4 devoid cells was substantially reduced by reintroducing wild-type PC4 to the cells but not the mutant PC4 (PC4K80R), defective in KAT5-mediated acetylation. High-resolution microscopy techniques, including transmission electron microscopy and atomic force microscopy, are employed to visualize chromatin structural changes in response to DNA damage and repair in a Tip60-mediated PC4 acetylation-dependent manner. Presumably, KAT5-mediated acetylation of PC4 at K80 residue facilitates access to the damaged DNA by altering chromatin structures at damage sites, thus promoting DNA repair. This process could be highly significant both in cancer and in aging.