Acetylation of PCNA Sliding Surface by Eco1 Promotes Genome Stability through Homologous Recombination

During DNA replication, proliferating cell nuclear antigen (PCNA) adopts a ring-shaped structure to promote processive DNA synthesis, acting as a sliding clamp for polymerases. Known posttranslational modifications function at the outer surface of the PCNA ring to favor DNA damage bypass. Here, we demonstrate that acetylation of lysine residues at the inner surface of PCNA is induced by DNA lesions. We show that cohesin acetyltransferase Eco1 targets lysine 20 at the sliding surface of the PCNA ring in vitro and in vivo in response to DNA damage. Mimicking constitutive acetylation stimulates homologous recombination and robustly suppresses the DNA damage sensitivity of mutations in damage tolerance pathways. In comparison to the unmodified trimer, structural differences are observed at the interface between protomers in the crystal structure of the PCNA-K20ac ring. Thus, acetylation regulates PCNA sliding on DNA in the presence of DNA damage, favoring homologous recombination linked to sister-chromatid cohesion. [Display omitted] •The PCNA ring is acetylated at its sliding surface in response to DNA damage•Eco1, the cohesin-associated acetyltransferase, targets PCNA on lysine 20•PCNA-K20ac suppresses DNA damage sensitivity of mutations in tolerance pathways•PCNA-K20ac ring shows structural differences and stimulates homologous recombination Billon et al. identify lysine acetylation as a regulatory modification at the inner surface of proliferative cell nuclear antigen (PCNA). DNA damage induces Eco1-mediated acetylation of PCNA at lysine 20, which stimulates repair by sister-chromatid-mediated homologous recombination.