HMCES Maintains Genome Integrity by Shielding Abasic Sites in Single-Strand DNA

Cell. 2019 Jan 10;176(1-2):144-153.e13. doi: 10.1016/j.cell.2018.10.055. Epub 2018 Dec 13.


Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation. Acting as a suicide enzyme, HMCES prevents translesion DNA synthesis and the action of endonucleases that would otherwise generate mutations and double-strand breaks. HMCES is evolutionarily conserved in all domains of life, and its biochemical properties are shared with its E. coli ortholog. Thus, HMCES is an ancient DNA lesion recognition protein that preserves genome integrity by promoting error-free repair of abasic sites in single-stranded DNA.

Keywords: 5-hydroxymethylcytosine; DNA repair; DNA replication; DNA-protein crosslink; HMCES; PCNA; REV1; SRAP; replication stress; translesion DNA synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives*
  • 5-Methylcytosine / metabolism
  • Apurinic Acid / metabolism
  • DNA / metabolism
  • DNA Damage / physiology
  • DNA Repair / physiology*
  • DNA Replication / physiology
  • DNA, Single-Stranded / metabolism
  • DNA, Single-Stranded / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endonucleases
  • Escherichia coli / metabolism
  • Polynucleotides / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism


  • DNA, Single-Stranded
  • DNA-Binding Proteins
  • Polynucleotides
  • Proliferating Cell Nuclear Antigen
  • apyrimidinic acid
  • Apurinic Acid
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • DNA
  • Endonucleases