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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.

The replicative DNA helicase lies at the heart of the eukaryotic replication machine, yet how it works remains puzzling. New structures of the viral replicative helicase SV40 T antigen suggest that a novel concerted mode of nucleotide binding and hydrolysis powers conformation changes and DNA unwinding.

The replicative DNA helicase lies at the heart of the eukaryotic replication machine, yet how it works remains puzzling. New structures of the viral replicative helicase SV40 T antigen (Gai et al., 2004 [this issue of Cell]) suggest that a novel concerted mode of nucleotide binding and hydrolysis powers conformation changes and DNA unwinding.