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

Halabelian, Levon; Ravichandran, Mani; Li, Yanjun; Zeng, Hong; Rao, Anjana; Aravind, L.; Arrowsmith, Cheryl H.

doi:10.1038/s41594-019-0246-6

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

Journal Article · Mon Jun 24 00:00:00 EDT 2019 · Nature Structural & Molecular Biology

DOI:https://doi.org/10.1038/s41594-019-0246-6· OSTI ID:1543001

^[1]; Ravichandran, Mani ^[1];

^[1]; Zeng, Hong ^[1]; Rao, Anjana ^[2]; Aravind, L. ^[3];

^[4]

Univ. of Toronto, ON (Canada)
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)
National Inst. of Health (NIH), Bethesda, MD (United States). National Center for Biotechnology Information and National Library of Medicine
Univ. of Toronto, ON (Canada); University Health Network, Toronto, ON (Canada)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); 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)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; S10 RR029205

OSTI ID:: 1543001

Journal Information:: Nature Structural & Molecular Biology, Vol. 26, Issue 7; ISSN 1545-9993

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 29 works

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Cited By (1)

Molecular basis of abasic site sensing in single-stranded DNA by the SRAP domain of E. coli yedK Wang, Na; Bao, Hongyu; Chen, Liu Nucleic Acids Research, Vol. 47, Issue 19 https://doi.org/10.1093/nar/gkz744	journal	August 2019

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59 BASIC BIOLOGICAL SCIENCES
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