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bioRxiv · 10.1101/2021.07.29.454365

The HMCES DNA-protein cross-link functions as a constitutive DNA repair intermediate

Semlow, D. R.·MacKrell, V. A.·Walter, J.
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Abstract

The HMCES protein forms a covalent DNA-protein cross-link (DPC) with abasic (AP) sites in ssDNA, and the resulting HMCES-DPC is thought to suppress double-strand break formation in S phase. However, the dynamics of HMCES cross-linking and whether any DNA repair pathways normally include an HMCES-DPC intermediate remain unknown. Here, we show that an HMCES-DPC forms efficiently on the AP site generated during replication-coupled DNA interstrand cross-link (ICL) repair. We use this system to show that HMCES cross-links form on DNA after the replicative CMG helicase has passed over the AP site, and that HMCES is subsequently removed by the SPRTN protease. The HMCES-DPC suppresses DSB formation, slows translesion synthesis (TLS) past the AP site, and introduces a bias for insertion of deoxyguanosine opposite the AP site. These data show that HMCES-DPCs can form as constitutive intermediates in replication-coupled repair, and they suggest a general model of how HMCES protects AP sites during DNA replication.

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Semlow, D. R., MacKrell, V. A., Walter, J.. 2021-07-29. The HMCES DNA-protein cross-link functions as a constitutive DNA repair intermediate. https://doi.org/10.1101/2021.07.29.454365

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