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

Mol Cell. 2017 Jan 5;65(1):78-90. doi: 10.1016/j.molcel.2016.10.033. Epub 2016 Dec 1.

Abstract

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.

Keywords: DNA polymerases; Eco1; PCNA; homologous recombination; lysine acetylation; translesion synthesis.

MeSH terms

  • Acetylation
  • Acetyltransferases / chemistry
  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism*
  • Chromatids*
  • Chromosomes, Fungal*
  • DNA Damage*
  • DNA Polymerase III / genetics
  • DNA Polymerase III / metabolism
  • Genomic Instability*
  • Genotype
  • Humans
  • Lysine
  • Models, Molecular
  • Mutation
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phenotype
  • Proliferating Cell Nuclear Antigen / chemistry
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Protein Conformation
  • Protein Processing, Post-Translational*
  • Recombinational DNA Repair*
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Structure-Activity Relationship

Substances

  • Nuclear Proteins
  • POL30 protein, S cerevisiae
  • Proliferating Cell Nuclear Antigen
  • Saccharomyces cerevisiae Proteins
  • Acetyltransferases
  • ECO1 protein, S cerevisiae
  • DNA Polymerase III
  • Lysine