Structural basis of HMCES interactions with DNA reveals multivalent substrate recognition

HMCES can covalently crosslink to abasic sites in single-stranded DNA at stalled replication forks to prevent genome instability. Here, we report crystal structures of the HMCES SRAP domain in complex with DNA-damage substrates, revealing interactions with both single-stranded and duplex segments of 3′ overhang DNA. HMCES may also bind gapped DNA and 5′ overhang structures to align single stranded abasic sites for crosslinking to the conserved Cys2 of its catalytic triad.