UV-induced RPA1 Acetylation Promotes Nucleotide Excision Repair

The intergrity of genomic DNA is continuously challenged by both exogenous and endogenous DNA-damaging agents.About 104-105 DNA lesions occurper cell per day in humans.The misrepaired or unrepaired DNA damage will finally result ingenomic instability and disease.To maintaingenome stability,cells have evolved the DNA damage response(DDR)system to cope with continuous DNA damages.The DDR comprises DNA damage recognition,DDR protein recruitment,cell cycle arrest and DNA repair.One of the important repair pathways is nucleotide excision repair(NER),which is responsible for removal of bulky DNA lesions included by UV irradiation damage.Replication protein A(RPA)is pivotal in the nucleotide excision repair pathway through interaction with several key NER factors including XPA.However,how these interactions are regulated remains unclear.Emerging evidence suggests that protein-translational modification(PTM)may play important roles in the regulation of either RPA function or NER process.Here,we provide evidence that the large subunit of RPA complex(RPA1)could be acetylated on lysine 163 by the lysine acetyltransferase GCN5/PCAF and deacetylated by HDAC6/SIRT1.RPA1 acetylation is only observed upon UV-irradiation but not under replication stress,which strongly suggested a role of RPA 1 acetylation in NER.Mechanistically,UV exposure promotes nuclear exporting of HDAC6,followed with RPA1 acetylation and stronger association between RPA and XPA,which finally promotes the completion of NER.