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

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 se...

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Autores principales: Zhao, Junhua, Jain, Aklank, Iyer, Ravi R., Modrich, Paul L., Vasquez, Karen M.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715249/
https://www.ncbi.nlm.nih.gov/pubmed/19468048
http://dx.doi.org/10.1093/nar/gkp399
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author Zhao, Junhua
Jain, Aklank
Iyer, Ravi R.
Modrich, Paul L.
Vasquez, Karen M.
author_facet Zhao, Junhua
Jain, Aklank
Iyer, Ravi R.
Modrich, Paul L.
Vasquez, Karen M.
author_sort Zhao, Junhua
collection PubMed
description 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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spelling pubmed-27152492009-07-24 Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks Zhao, Junhua Jain, Aklank Iyer, Ravi R. Modrich, Paul L. Vasquez, Karen M. Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2009-07 2009-05-25 /pmc/articles/PMC2715249/ /pubmed/19468048 http://dx.doi.org/10.1093/nar/gkp399 Text en © 2009 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ 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.
spellingShingle Genome Integrity, Repair and Replication
Zhao, Junhua
Jain, Aklank
Iyer, Ravi R.
Modrich, Paul L.
Vasquez, Karen M.
Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks
title Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks
title_full Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks
title_fullStr Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks
title_full_unstemmed Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks
title_short Mismatch repair and nucleotide excision repair proteins cooperate in the recognition of DNA interstrand crosslinks
title_sort mismatch repair and nucleotide excision repair proteins cooperate in the recognition of dna interstrand crosslinks
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715249/
https://www.ncbi.nlm.nih.gov/pubmed/19468048
http://dx.doi.org/10.1093/nar/gkp399
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