KAT5 Acetylates Human Chromatin Protein PC4 to promote DNA Repair

Abstract

Human positive coactivator 4 (PC4), is a highly abundant non-histone chromatin protein involved in diverse cellular processes, including transcription regulation, genome organization, DNA repair, etc. The majority of PC4 exists in a phosphorylated state in cells, which impinges its acetylation by p300 and thereby inhibits its double-stranded DNA binding ability and transcriptional co-activator function. Recently, we have shown that PC4 interacts with linker histone H1 in its phosphorylated state, and this interaction is important for PC4- mediated chromatin compaction. PC4 was also found to be an activator of non-homologous end joining and DSB repair activity. Knockdown of PC4 causes drastic decompaction and enhanced autophagy in the cells. Mechanistically, in the absence of PC4, the genome becomes highly vulnerable to DNA damage with an altered epigenetic landscape. Here, we report that other than p300, PC4 also gets acetylated by DNA repair facilitating lysine acetyltransferase KAT5 (Tip60), at K80 residue when the cells are subjected to DNA damage. The vulnerability of DNA in PC4 devoid cells could be substantially reduced by reintroducing wild-type PC4 to the cells but not the mutant PC4 (K80R PC4), defective in KAT5-mediated acetylation. Presumably, KAT5-mediated acetylation of PC4 at K80 residue facilitates the DNA repair machinery at the damage site and thus contributes to DNA damage repair, a process that could be of high significance both in cancer and in aging.