Format

Send to

Choose Destination
Nat Struct Mol Biol. 2019 Jul;26(7):613-618. doi: 10.1038/s41594-019-0255-5. Epub 2019 Jun 24.

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

Author information

1
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
2
Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
3
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA. david.cortez@vanderbilt.edu.
4
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA. brandt.eichman@vanderbilt.edu.
5
Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA. brandt.eichman@vanderbilt.edu.

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. 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.

PMID:
31235915
DOI:
10.1038/s41594-019-0255-5

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center