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

Semlow, Daniel R. and MacKrell, Victoria A. and Walter, Johannes C. (2021) The HMCES DNA-protein cross-link functions as a constitutive DNA repair intermediate. . (Unpublished)

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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.

Item Type:Report or Paper (Discussion Paper)
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Walter, Johannes C.0000-0002-4186-7570
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted July 29, 2021. Data availability statement: All data supporting the findings of this study are available within the article and its supplementary information files. Unprocessed and uncropped gel and blot images are available from the corresponding authors upon request. The authors have declared no competing interest.
Record Number:CaltechAUTHORS:20210803-144719750
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Official Citation:The HMCES DNA-protein cross-link functions as a constitutive DNA repair intermediate. Daniel R. Semlow, Victoria A. MacKrell, Johannes C. Walter. bioRxiv 2021.07.29.454365; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110124
Deposited By: Tony Diaz
Deposited On:04 Aug 2021 18:35
Last Modified:16 Nov 2021 19:39

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