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

Cell | 2019

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.

Pubmed ID: 30554877 RIS Download

Research resources used in this publication

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: T32 CA009582
  • Agency: NCI NIH HHS, United States
    Id: P01 CA092584
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007347
  • Agency: NIGMS NIH HHS, United States
    Id: F32 GM126646
  • Agency: NCI NIH HHS, United States
    Id: F30 CA228242
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM116616

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