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Title: Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link

Abstract

Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. 5-hydroxymethylcytosine binding, embryonic stem cell-specific protein (HMCES) recognizes and processes these lesions in the context of single-stranded DNA (ssDNA). A HMCES DNA-protein cross-link (DPC) intermediate is thought to shield the AP site from endonucleases and error-prone polymerases. The highly evolutionarily conserved SOS-response associated peptidase (SRAP) domain of HMCES and its Escherichia coli ortholog YedK mediate lesion recognition. Here we uncover the basis of AP site protection by SRAP domains from a crystal structure of the YedK DPC. We report YedK forms a stable thiazolidine linkage between a ring-opened AP site and the α-amino and sulfhydryl substituents of its amino-terminal cysteine residue. The thiazolidine linkage explains the remarkable stability of the HMCES DPC, its resistance to strand cleavage and the proteolysis requirement for resolution. Furthermore, its structure reveals that HMCES has specificity for AP sites in ssDNA at junctions found when replicative polymerases encounter the AP lesion.

Authors:
 [1]; ORCiD logo [2];  [1]; ORCiD logo [1]; ORCiD logo [3]
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  2. Vanderbilt Univ., Nashville, TN (United States)
  3. Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Vanderbilt Molecular Biophysics Training Program; Vanderbilt-Ingram Cancer Center; USDOE Office of Science (SC), Basic Energy Sciences (BES); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor
OSTI Identifier:
1544876
Grant/Contract Number:  
R01ES030575; R01GM117299; P01CA092584; AC02-06CH11357; 085P1000817
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; Biochemistry; DNA; Enzyme mechanisms; Structural biology

Citation Formats

Thompson, Petria S., Amidon, Katherine M., Mohni, Kareem N., Cortez, David, and Eichman, Brandt F. Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link. United States: N. p., 2019. Web. doi:10.1038/s41594-019-0255-5.
Thompson, Petria S., Amidon, Katherine M., Mohni, Kareem N., Cortez, David, & Eichman, Brandt F. Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link. United States. https://doi.org/10.1038/s41594-019-0255-5
Thompson, Petria S., Amidon, Katherine M., Mohni, Kareem N., Cortez, David, and Eichman, Brandt F. Mon . "Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link". United States. https://doi.org/10.1038/s41594-019-0255-5. https://www.osti.gov/servlets/purl/1544876.
@article{osti_1544876,
title = {Protection of abasic sites during DNA replication by a stable thiazolidine protein-DNA cross-link},
author = {Thompson, Petria S. and Amidon, Katherine M. and Mohni, Kareem N. and Cortez, David and Eichman, Brandt F.},
abstractNote = {Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. 5-hydroxymethylcytosine binding, embryonic stem cell-specific protein (HMCES) recognizes and processes these lesions in the context of single-stranded DNA (ssDNA). A HMCES DNA-protein cross-link (DPC) intermediate is thought to shield the AP site from endonucleases and error-prone polymerases. The highly evolutionarily conserved SOS-response associated peptidase (SRAP) domain of HMCES and its Escherichia coli ortholog YedK mediate lesion recognition. Here we uncover the basis of AP site protection by SRAP domains from a crystal structure of the YedK DPC. We report YedK forms a stable thiazolidine linkage between a ring-opened AP site and the α-amino and sulfhydryl substituents of its amino-terminal cysteine residue. The thiazolidine linkage explains the remarkable stability of the HMCES DPC, its resistance to strand cleavage and the proteolysis requirement for resolution. Furthermore, its structure reveals that HMCES has specificity for AP sites in ssDNA at junctions found when replicative polymerases encounter the AP lesion.},
doi = {10.1038/s41594-019-0255-5},
journal = {Nature Structural & Molecular Biology},
number = 7,
volume = 26,
place = {United States},
year = {2019},
month = {6}
}

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Works referencing / citing this record:

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