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Reviewer Report by Maximilian Donsbach; Sophie Dürauer; Florian Grünert; Kha T Nguyen; Richa Nigam; Denitsa Yaneva; Pedro Weickert; Rachel Bezalel‐Buch; Daniel R Semlow; Julian Stingele is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## Abstract The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we report a non‐proteolytic release mechanism for HMCES‐DNA‐protein crosslinks (DPCs), which is regulated by DNA context. In ssDNA and at ssDNA‐dsDNA junctions, HMCES‐DPCs are stable, which efficiently protects AP sites against spontaneous incisions or cleavage by APE1 endonuclease. In contrast, HMCES‐DPCs are released in dsDNA, allowing APE1 to initiate downstream repair. Mechanistically, we show that release is governed by two components. First, a conserved glutamate residue, within HMCES' active site, catalyses reversal of the crosslink. Second, affinity to the underlying DNA structure determines whether HMCES re‐crosslinks or dissociates. Our study reveals that the protective role of HMCES‐DPCs involves their controlled release upon bypass by replication forks, which restricts DPC formation to a necessary minimum.

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Author

Maximilian Donsbach; Sophie Dürauer; Florian Grünert; Kha T Nguyen; Richa Nigam; Denitsa Yaneva; Pedro Weickert; Rachel Bezalel‐Buch; Daniel R Semlow; Julian Stingele

Publisher

EMBO

Published

2023

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)