Abstract
PCAF (p300-associated factor), a major histone acetyltransferase, is involved in many metabolic and pathogenic diseases. Here, we reveal a novel function of PCAF in homologous recombination repair (HR). We demonstrate that RAD51, a core protein in HR repair, physically interacts with the acetyltransferase domain of PCAF and is acetylated at lysine 40. This acetylation promotes RAD51 binding to ubiquitin, leading to its degradation via the ubiquitin-proteasome pathway. Following etoposide treatment, PCAF-induced acetylation removes RAD51 from chromatin to facilitate the late-phase HR processes. Overexpression of PCAF promotes premature dissociation of RAD51 from DNA damage sites. Notably, PCAF is downregulated in many cancers compared to adjacent tissues, correlating with shortened patient survival. Our findings suggest that decreased PCAF expression enhances HR efficiency, contributing to drug resistance in tumor cells, and the impact of PCAF on HR is dependent on its acetyltransferase activity. Our results highlight a novel role of PCAF in HR and provide a possible mechanism for tumor development and drug resistance caused by low expression of PCAF.