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      Human MLH1 Protein Participates in Genomic Damage Checkpoint Signaling in Response to DNA Interstrand Crosslinks, while MSH2 Functions in DNA Repair

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      PLoS Genetics
      Public Library of Science

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          Abstract

          DNA interstrand crosslinks (ICLs) are among the most toxic types of damage to a cell. For this reason, many ICL-inducing agents are effective therapeutic agents. For example, cisplatin and nitrogen mustards are used for treating cancer and psoralen plus UVA (PUVA) is useful for treating psoriasis. However, repair mechanisms for ICLs in the human genome are not clearly defined. Previously, we have shown that MSH2, the common subunit of the human MutSα and MutSβ mismatch recognition complexes, plays a role in the error-free repair of psoralen ICLs. We hypothesized that MLH1, the common subunit of human MutL complexes, is also involved in the cellular response to psoralen ICLs. Surprisingly, we instead found that MLH1-deficient human cells are more resistant to psoralen ICLs, in contrast to the sensitivity to these lesions displayed by MSH2-deficient cells. Apoptosis was not as efficiently induced by psoralen ICLs in MLH1-deficient cells as in MLH1-proficient cells as determined by caspase-3/7 activity and binding of annexin V. Strikingly, CHK2 phosphorylation was undetectable in MLH1-deficient cells, and phosphorylation of CHK1 was reduced after PUVA treatment, indicating that MLH1 is involved in signaling psoralen ICL-induced checkpoint activation. Psoralen ICLs can result in mutations near the crosslinked sites; however, MLH1 function was not required for the mutagenic repair of these lesions, and so its signaling function appears to have a role in maintaining genomic stability following exposure to ICL-induced DNA damage. Distinguishing the genetic status of MMR-deficient tumors as MSH2-deficient or MLH1-deficient is thus potentially important in predicting the efficacy of treatment with psoralen and perhaps with other ICL-inducing agents.

          Author Summary

          Crosslinks, linking the complementary stands of the DNA double helix, can lead to cell death, because they are so effective at interfering with normal genomic transactions such as DNA replication. This property of crosslinking agents has long been utilized in cancer therapy. The purpose of our research is to understand the function of DNA repair proteins in cellular responses to DNA interstrand crosslinking agents. MSH2 is a central protein in the recognition of DNA mismatches, and we previously found that it plays an important role in protecting cells against the toxicity of crosslinks. The MLH1 protein functions in DNA mismatch repair in a later step, and we hypothesized that MLH1 may also be involved in repair of crosslinks. We were surprised to find that MLH1 function is important for DNA crosslink-induced signaling, rather than DNA repair. MLH1-deficient cells are more resistant to crosslinks and have defective signaling to processes that signal cell death. This work may have clinical consequences, as mutations in MSH2 and MLH1 are common in tumors. MSH2-deficient cells may be more vulnerable to DNA crosslink-inducing agents than normal, while MLH1-deficient cells have a greater potential to survive crosslinking treatment, which could instead potentiate further tumor initiation.

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          Most cited references51

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          The multifaceted mismatch-repair system.

          By removing biosynthetic errors from newly synthesized DNA, mismatch repair (MMR) improves the fidelity of DNA replication by several orders of magnitude. Loss of MMR brings about a mutator phenotype, which causes a predisposition to cancer. But MMR status also affects meiotic and mitotic recombination, DNA-damage signalling, apoptosis and cell-type-specific processes such as class-switch recombination, somatic hypermutation and triplet-repeat expansion. This article reviews our current understanding of this multifaceted DNA-repair system in human cells.
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            • Record: found
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            DNA mismatch repair: functions and mechanisms.

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              • Abstract: found
              • Article: not found

              Mismatch repair in replication fidelity, genetic recombination, and cancer biology.

              Mismatch repair stabilizes the cellular genome by correcting DNA replication errors and by blocking recombination events between divergent DNA sequences. The reaction responsible for strand-specific correction of mispaired bases has been highly conserved during evolution, and homologs of bacterial MutS and MutL, which play key roles in mismatch recognition and initiation of repair, have been identified in yeast and mammalian cells. Inactivation of genes encoding these activities results in a large increase in spontaneous mutability, and in the case of mice and men, predisposition to tumor development.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                September 2008
                September 2008
                12 September 2008
                : 4
                : 9
                : e1000189
                Affiliations
                [1]Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, United States of America
                Stanford University School of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: QW KMV. Performed the experiments: QW. Analyzed the data: QW KMV. Contributed reagents/materials/analysis tools: QW KMV. Wrote the paper: QW KMV.

                Article
                08-PLGE-RA-0314R2
                10.1371/journal.pgen.1000189
                2526179
                18787700
                a9ccabd9-46e3-4b18-8585-f1d5f4bb92f5
                Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 19 March 2008
                : 5 August 2008
                Page count
                Pages: 10
                Categories
                Research Article
                Biochemistry/Replication and Repair
                Cell Biology/Cell Signaling
                Cell Biology/Cellular Death and Stress Responses
                Genetics and Genomics/Cancer Genetics
                Genetics and Genomics/Gene Function
                Genetics and Genomics/Nuclear Structure and Function
                Molecular Biology/DNA Repair

                Genetics
                Genetics

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