2. Academic Validation
  3. Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition

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

  • Nat Struct Mol Biol. 2019 Jul;26(7):607-612. doi: 10.1038/s41594-019-0246-6.
Levon Halabelian 1,  Mani Ravichandran 1,  Yanjun Li 1,  Hong Zeng 1,  Anjana Rao 2 3 4 5,  L Aravind 6 7,  Cheryl H Arrowsmith 8 9 10
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 2 Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA.
  • 3 Department of Pharmacology, University of San Diego, La Jolla, CA, USA.
  • 4 Moores Cancer Center, University of San Diego, La Jolla, CA, USA.
  • 5 Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA.
  • 6 National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, USA.
  • 7 National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
  • 8 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. cheryl.arrowsmith@uhnresearch.ca.
  • 9 Department of Medical Biophysics, University of Toronto, Toronto, Onatario, Canada. cheryl.arrowsmith@uhnresearch.ca.
  • 10 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. cheryl.arrowsmith@uhnresearch.ca.
PMID: 31235913 DOI: 10.1038/s41594-019-0246-6
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, 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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