Role of mismatch repair proteins in the processing of cisplatin interstrand cross-links |
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| Affiliation: | 1. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands;2. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA;3. Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia;4. Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark;5. Department of Genetics and Computational Biology, QIMR BerghoferMedical Research Institute, Brisbane, Australia;6. Department of Microbiology and Molecular Genetics, University of Vermont Robert Larner, M.D. College of Medicine, Burlington, VT, USA;7. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;8. Department of Medicine, Division of Epidemiology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA;9. Department of Clinical Genetics, Leiden UniversityMedical Center, Leiden, The Netherlands;10. Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA;11. Department of Medicine and University of Vermont Cancer Center, University of Vermont Robert Larner, M.D. College of Medicine, Burlington, VT, USA. |
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| Abstract: | Mismatch repair (MMR) deficiency gives rise to cisplatin resistance and can lead to poor prognosis in cancers. Various models have been proposed to explain this low level of resistance caused due to loss of MMR proteins. We have shown that MMR proteins are required to maintain cisplatin interstrand cross-links (ICLs) on the DNA leading to increased cellular sensitivity. In our previous studies, we have shown that BER processing of the cisplatin ICLs is mutagenic. Polymerase β (Polβ) can generate mismatches which leads to the activation and the recruitment of mismatch repair proteins. In this paper, we distinguished between the requirement of different downstream MMR proteins for maintaining cisplatin sensitivity. We show that the MutSα (MSH2–MSH6) heterocomplex is required to maintain cisplatin sensitivity, whereas the Mutsβ complex has no effect. These results can be correlated with the increased repair of cisplatin ICLs and ICL induced DNA double strand breaks (DSBs) in the resistant cells. Moreover, we show that MLH1 proficient cells displayed a cisplatin sensitive phenotype when compared with the MLH1 deficient cells and the ATPase activity of MLH1 is essential to mediate this effect. Based on these results, we propose that MutSα as well as the downstream MMR pathway proteins are essential to maintain a cisplatin sensitive phenotype as a consequence of processing Polβ induced mismatches at sites flanking cisplatin ICLs. |
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| Keywords: | BER Cisplatin MMR Resistance ATPase |
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