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Nucleic Acids Research Advance Access published online on May 25, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp399
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair and Replication

Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks

Junhua Zhao1, Aklank Jain1, Ravi R. Iyer2, Paul L. Modrich2 and Karen M. Vasquez1,*

1Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science-Park Research Division, Smithville, TX 78957 and 2Department of Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA

*To whom correspondence should be addressed. Tel: +1 512 237 9324; Fax: +1 512 237 2475; Email: kvasquez{at}mdanderson.org

Received March 16, 2009. Revised April 30, 2009. Accepted May 3, 2009.

DNA interstrand crosslinks (ICLs) are among the most cytotoxic types of DNA damage, thus ICL-inducing agents such as psoralen, are clinically useful chemotherapeutics. Psoralen-modified triplex-forming oligonucleotides (TFOs) have been used to target ICLs to specific genomic sites to increase the selectivity of these agents. However, how TFO-directed psoralen ICLs (Tdp-ICLs) are recognized and processed in human cells is unclear. Previously, we reported that two essential nucleotide excision repair (NER) protein complexes, XPA–RPA and XPC–RAD23B, recognized ICLs in vitro, and that cells deficient in the DNA mismatch repair (MMR) complex MutSβ were sensitive to psoralen ICLs. To further investigate the role of MutSβ in ICL repair and the potential interaction between proteins from the MMR and NER pathways on these lesions, we performed electrophoretic mobility-shift assays and chromatin immunoprecipitation analysis of MutSβ and NER proteins with Tdp-ICLs. We found that MutSβ bound to Tdp-ICLs with high affinity and specificity in vitro and in vivo, and that MutSβ interacted with XPA–RPA or XPC–RAD23B in recognizing Tdp-ICLs. These data suggest that proteins from the MMR and NER pathways interact in the recognition of ICLs, and provide a mechanistic link by which proteins from multiple repair pathways contribute to ICL repair.


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Y. Liu, R. S. Nairn, and K. M. Vasquez
Targeted gene conversion induced by triplex-directed psoralen interstrand crosslinks in mammalian cells
Nucleic Acids Res., October 1, 2009; 37(19): 6378 - 6388.
[Abstract] [Full Text] [PDF]


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