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Title: Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition

Abstract

Embryonic stem cell-specific 5-hydroxymethylcytosine-binding protein (HMCES) can covalently cross-link to abasic sites in single-stranded DNA at stalled replication forks to prevent genome instability. Here, in this paper, we report crystal structures of the human HMCES SOS response-associated peptidase (SRAP) domain in complex with DNA-damage substrates, including HMCES cross-linked with an abasic site within a 3' overhang DNA. HMCES interacts with both single-strand and duplex segments of DNA, with two independent duplex DNA interaction sites identified in the SRAP domain. The HMCES DNA-protein cross-link structure provides structural insights into a novel thiazolidine covalent interaction between the DNA abasic site and conserved Cys 2 of HMCES. Collectively, our structures demonstrate the capacity for the SRAP domain to interact with a variety of single-strand- and double-strand-containing DNA structures found in DNA-damage sites, including 5' and 3' overhang DNAs and gapped DNAs with short single-strand segments.

Authors:
ORCiD logo [1];  [1]; ORCiD logo [1];  [1];  [2];  [3]; ORCiD logo [4]
  1. Univ. of Toronto, ON (Canada)
  2. La Jolla Inst. for Immunology, CA (United States); Univ. of San Diego, La Jolla, CA (United States); Sanford Consortium for Regenerative Medicine, La Jolla, CA (United States)
  3. National Inst. of Health (NIH), Bethesda, MD (United States). National Center for Biotechnology Information and National Library of Medicine
  4. Univ. of Toronto, ON (Canada); University Health Network, Toronto, ON (Canada)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Canadian Institutes of Health Research (CIHR); Natural Sciences and Engineering Research Council of Canada (NSERC); National Library of Medicine (NLM); National Cancer Institute (NCI)
OSTI Identifier:
1543001
Grant/Contract Number:  
AC02-05CH11231; AC02-06CH11357; S10 RR029205
Resource Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 26; Journal Issue: 7; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Base excision repair; X-ray crystallography

Citation Formats

Halabelian, Levon, Ravichandran, Mani, Li, Yanjun, Zeng, Hong, Rao, Anjana, Aravind, L., and Arrowsmith, Cheryl H. Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition. United States: N. p., 2019. Web. doi:10.1038/s41594-019-0246-6.
Halabelian, Levon, Ravichandran, Mani, Li, Yanjun, Zeng, Hong, Rao, Anjana, Aravind, L., & Arrowsmith, Cheryl H. Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition. United States. doi:10.1038/s41594-019-0246-6.
Halabelian, Levon, Ravichandran, Mani, Li, Yanjun, Zeng, Hong, Rao, Anjana, Aravind, L., and Arrowsmith, Cheryl H. Mon . "Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition". United States. doi:10.1038/s41594-019-0246-6.
@article{osti_1543001,
title = {Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition},
author = {Halabelian, Levon and Ravichandran, Mani and Li, Yanjun and Zeng, Hong and Rao, Anjana and Aravind, L. and Arrowsmith, Cheryl H.},
abstractNote = {Embryonic stem cell-specific 5-hydroxymethylcytosine-binding protein (HMCES) can covalently cross-link to abasic sites in single-stranded DNA at stalled replication forks to prevent genome instability. Here, in this paper, we report crystal structures of the human HMCES SOS response-associated peptidase (SRAP) domain in complex with DNA-damage substrates, including HMCES cross-linked with an abasic site within a 3' overhang DNA. HMCES interacts with both single-strand and duplex segments of DNA, with two independent duplex DNA interaction sites identified in the SRAP domain. The HMCES DNA-protein cross-link structure provides structural insights into a novel thiazolidine covalent interaction between the DNA abasic site and conserved Cys 2 of HMCES. Collectively, our structures demonstrate the capacity for the SRAP domain to interact with a variety of single-strand- and double-strand-containing DNA structures found in DNA-damage sites, including 5' and 3' overhang DNAs and gapped DNAs with short single-strand segments.},
doi = {10.1038/s41594-019-0246-6},
journal = {Nature Structural & Molecular Biology},
number = 7,
volume = 26,
place = {United States},
year = {2019},
month = {6}
}

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