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Peggy Hsieh - One of the best experts on this subject based on the ideXlab platform.

  • DNA Mismatch Repair and the DNA damage response.
    DNA Repair, 2015
    Co-Authors: Alexander H. Pearlman, Peggy Hsieh
    Abstract:

    This review discusses the role of DNA Mismatch Repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1,2]. MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted.

  • DNA Mismatch Repair: Dr. Jekyll and Mr. Hyde?
    Molecular Cell, 2012
    Co-Authors: Peggy Hsieh
    Abstract:

    In this issue, Pena-Diaz et al. (2012) describe a pathway for somatic mutation in nonlymphoid cells termed noncanonical DNA Mismatch Repair, whereby the error-prone translesion polymerase Pol-η substitutes for high-fidelity replicative polymerases to resynthesize excised regions opposite DNA damage.

  • In vitro studies of DNA Mismatch Repair proteins.
    Analytical Biochemistry, 2011
    Co-Authors: Hui Geng, Chunwei Du, Siying Chen, Vincenzo Salerno, Candela Manfredi, Peggy Hsieh
    Abstract:

    Abstract The ability to monitor and characterize DNA Mismatch Repair activity in various mammalian cells is important for understanding mechanisms involved in mutagenesis and tumorigenesis. Since Mismatch Repair proteins recognize Mismatches containing both normal and chemically altered or damaged bases, in vitro assays must accommodate a variety of Mismatches in different sequence contexts. Here we describe the construction of DNA Mismatch substrates containing G:T or O6meG:T Mismatches, the purification of recombinant native human MutSα (MSH2–MSH6) and MutLα (MLH1–PMS2) proteins, and in vitro Mismatch Repair and excision assays that can be adapted to study Mismatch Repair in nuclear extracts from Mismatch Repair proficient and deficient cells.

  • DNA Mismatch Repair molecular mechanism cancer and ageing
    Mechanisms of Ageing and Development, 2008
    Co-Authors: Peggy Hsieh, Kazuhiko Yamane
    Abstract:

    DNA Mismatch Repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication Repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

  • DNA Mismatch Repair molecular mechanisms and biological function
    Annual Review of Microbiology, 2003
    Co-Authors: Mark J Schofield, Peggy Hsieh
    Abstract:

    DNA Mismatch Repair (MMR) guards the integrity of the genome in virtually all cells. It contributes about 1000-fold to the overall fidelity of replication and targets mispaired bases that arise through replication errors, during homologous recombination, and as a result of DNA damage. Cells deficient in MMR have a mutator phenotype in which the rate of spontaneous mutation is greatly elevated, and they frequently exhibit microsatellite instability at mono- and dinucleotide repeats. The importance of MMR in mutation avoidance is highlighted by the finding that defects in MMR predispose individuals to hereditary nonpolyposis colorectal cancer. In addition to its role in postreplication Repair, the MMR machinery serves to police homologous recombination events and acts as a barrier to genetic exchange between species.

Richard C Boland - One of the best experts on this subject based on the ideXlab platform.

  • an optimized pentaplex pcr for detecting DNA Mismatch Repair deficient colorectal cancers
    PLOS ONE, 2010
    Co-Authors: Ajay Goel, Takeshi Nagasaka, Richard Hamelin, Richard C Boland
    Abstract:

    Purpose Microsatellite instability (MSI) is used to screen colorectal cancers (CRC) for Lynch Syndrome, and to predict outcome and response to treatment. The current technique for measuring MSI requires DNA from normal and neoplastic tissues, and fails to identify tumors with specific DNA Mismatch Repair (MMR) defects. We tested a panel of five quasi-monomorphic mononucleotide repeat markers amplified in a single multiplex PCR reaction (pentaplex PCR) to detect MSI.

Victor A. Tron - One of the best experts on this subject based on the ideXlab platform.

  • DNA Mismatch Repair protein msh6 is required for optimal levels of ultraviolet b induced apoptosis in primary mouse fibroblasts
    Journal of Investigative Dermatology, 2003
    Co-Authors: Leah C. Young, Susan E. Andrew, Anthea C Peters, Tomoko Maeda, Raju Kucherlapati, Winfried Edelmann, Victor A. Tron
    Abstract:

    Recent data support a role for DNA Mismatch Repair in the cellular response to some forms of exogenous DNA damage beyond that of DNA Repair; cells with defective DNA Mismatch Repair have partial or complete failure to undergo apoptosis and/or G2M arrest following specific types of damage. We propose that the DNA Mismatch Repair Msh2/Msh6 heterodimer, responsible for the detection of DNA damage, promotes apoptosis in normal cells, thus protecting mammals from ultraviolet-induced malignant transformation. Using primary mouse embryonic fibroblasts derived from Msh6+/+ and Msh6–/– mice, we compare the response of DNA-Mismatch Repair-proficient and -deficient cells to ultraviolet B radiation. In the wild-type mouse embryonic fibroblasts, ultraviolet-B-induced increases in Msh6 protein levels were not dependent on p53. Msh6–/– mouse embryonic fibroblasts were significantly less sensitive to the cytotoxic effects of ultraviolet B radiation. Further comparison of the Msh6+/+ and Msh6–/– mouse embryonic fibroblasts revealed that Msh6–/– mouse embryonic fibroblasts undergo significantly less apoptosis following ultraviolet B irradiation, thus indicating that ultraviolet-B-induced apoptosis is partially Msh6 dependent. These data support a role for Msh6 in protective cellular responses of primary cells to ultraviolet-B-induced mutagenesis and, hence, the prevention of skin cancer.

  • DNA Mismatch Repair Proteins: Potential Guardians Against Genomic Instability and Tumorigenesis Induced by Ultraviolet Photoproducts
    Journal of Investigative Dermatology, 2003
    Co-Authors: Leah C. Young, Victor A. Tron, John B. Hays, Susan E. Andrew
    Abstract:

    In addition to their established role in Repairing post-replicative DNA errors, DNA Mismatch Repair proteins contribute to cell cycle arrest and apoptosis in response to a wide range of exogenous DNA damage (e.g., alkylation-induced lesions). The role of DNA Mismatch Repair in response to ultraviolet-induced DNA damage has been historically controversial. Recent data, however, suggest that DNA Mismatch Repair proteins probably do not contribute to the removal of ultraviolet-induced DNA damage, but may be important in suppressing mutagenesis, effecting apoptosis, and suppressing tumorigenesis following exposure to ultraviolet radiation.

Kazuhiko Yamane - One of the best experts on this subject based on the ideXlab platform.

  • DNA Mismatch Repair molecular mechanism cancer and ageing
    Mechanisms of Ageing and Development, 2008
    Co-Authors: Peggy Hsieh, Kazuhiko Yamane
    Abstract:

    DNA Mismatch Repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication Repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

Daniel Fink - One of the best experts on this subject based on the ideXlab platform.

  • Photodynamic therapy of DNA Mismatch Repair-deficient and -proficient tumour cells
    British Journal of Cancer, 2002
    Co-Authors: V A Schwarz, René Hornung, André Fedier, Mathias K. Fehr, Heinrich Walt, Urs Haller, Daniel Fink
    Abstract:

    Loss of DNA Mismatch Repair is a common finding in hereditary nonpolyposis colon cancer as well as in many types of sporadic human tumours. DNA Mismatch Repair-deficient cells have been reported to be resistant to many chemotherapeutic agents and to radiotherapy, and to have the potential of rapidly acquiring additional mutations leading to tumour progression. Photodynamic therapy is a new treatment modality using light to activate a photosensitiser that preferentially localises in tumour cells. An oxygen dependent photochemical reaction ensues, resulting in selective tumour necrosis. The effect of loss of DNA Mismatch Repair activity on the sensitivity to photodynamic therapy was tested using pairs of cell lines proficient or deficient in Mismatch Repair due to loss of either MLH1 or MSH2 protein function. Cells were incubated with the photosensitiser 5,10,15,20-meta-tetra(hydroxyphenyl)chlorin and exposed to laser light at 652 nm with various optical doses ranging from 0-1 J cm(-2). Cell survival was assessed using the clonogenic assay. Loss of MLH1 or MSH2 function was not associated with resistance to photodynamic therapy. MCF-7 cells repeatedly treated with photodynamic therapy expressed parental levels of MLH1, MSH2, MSH6, and PMS2. DNA Mismatch Repair-deficient and -proficient cells showed similar subcellular distributions of meta-tetra(hydroxyphenyl)chlorin as analysed by laser scanning and fluorescence microscopy. Therefore, repeated exposure of tumour cells to photodynamic therapy does not seem to result in loss of DNA Mismatch Repair, and loss of Mismatch Repair, in turn, does not seem to contribute to resistance to photodynamic therapy. Our results suggest recommending photodynamic therapy as a strategy for circumventing resistance due to loss of DNA Mismatch Repair.

  • Resistance to topoisomerase poisons due to loss of DNA Mismatch Repair.
    International Journal of Cancer, 2001
    Co-Authors: André Fedier, Heinrich Walt, Urs Haller, Viola A. Schwarz, Renato Delli Carpini, Daniel Fink
    Abstract:

    Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA Mismatch Repair-deficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA Mismatch Repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA Mismatch Repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in Mismatch Repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poison-mediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA Mismatch Repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in Mismatch Repair. © 2001 Wiley-Liss, Inc.

  • The effect of different chemotherapeutic agents on the enrichment of DNA Mismatch Repair-deficient tumour cells
    British Journal of Cancer, 1998
    Co-Authors: Daniel Fink, Sibylle Nebel, Stefan Aebi, Paula S. Norris, Hk Kim, M Haas, Stephen B. Howell
    Abstract:

    Loss of DNA Mismatch Repair is a common finding in hereditary non-polyposis colon cancer as well as in many types of sporadic human tumours. We compared the effect of loss of DNA Mismatch Repair on drug sensitivity as measured by a clonogenic assay with its effect on the ability of the same drug to enrich for Mismatch Repair-deficient cells in a proliferating tumour cell population. Mixed populations containing 50% DNA Mismatch Repair-deficient cells constitutively expressing green fluorescent protein and 50% Mismatch Repair-proficient cells were exposed to different chemotherapeutic agents. 6-Thioguanine, to which DNA Mismatch Repair-deficient cells are known to be resistant, was included as a control. The results in the cytotoxicity assays and in the enrichment experiments were concordant. Treatment with either carboplatin, cisplatin, doxorubicin, etoposide or 6-thioguanine resulted in enrichment for Mismatch Repair-deficient cells, and clonogenic assays demonstrated resistance to these agents, which varied from 1.3- to 4.8-fold. Treatment with melphalan, paclitaxel, perfosfamide or tamoxifen failed to enrich for Mismatch Repair-deficient cells, and no change in sensitivity to these agents was detected in the clonogenic assays. These results identify the topoisomerase II inhibitors etoposide and doxorubicin as additional agents for which loss of DNA Mismatch Repair causes drug resistance. The concordance of the results from the two assay systems validates the enrichment assay as a rapid and reliable method for screening for the effect of loss of DNA Mismatch Repair on sensitivity to additional drugs.

  • Resistance to cytotoxic drugs in DNA Mismatch Repair-deficient cells
    Clinical Cancer Research, 1997
    Co-Authors: Stefan Aebi, Daniel Fink, Hua Zheng, Robert Gordon, Heung Ki Kim, J. L. Fink, Stephen B. Howell
    Abstract:

    Loss of DNA Mismatch Repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA Mismatch Repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in Mismatch Repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA Mismatch Repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.

  • Expression of the DNA Mismatch Repair proteins hMLH1 and hPMS2 in normal human tissues.
    British Journal of Cancer, 1997
    Co-Authors: Daniel Fink, Sibylle Nebel, Stefan Aebi, Hua Zheng, Randolph D. Christen, Hk Kim, Stephen B. Howell
    Abstract:

    hMLH1 and hPMS2 are part of the DNA Mismatch Repair complex. Mutations in these genes have been linked to hereditary non-polyposis colon cancer; they also occur in a variety of sporadic cancers. Western blot analysis and immunohistochemistry demonstrated that hMLH1 and hPMS2 are widely expressed nuclear proteins with a distribution pattern very similar to that previously described for hMSH2. These observations showing similar localization of hMLH1 and hPMS2 with hMSH2 are consistent with the biochemical function of these proteins in DNA Mismatch Repair.