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  1. Article ; Online: The mismatch repair-dependent DNA damage response: Mechanisms and implications.

    Gupta, Dipika / Heinen, Christopher D

    DNA repair

    2019  Volume 78, Page(s) 60–69

    Abstract: An important role for the DNA mismatch repair (MMR) pathway in maintaining genomic stability is embodied in its conservation through evolution and the link between loss of MMR function and tumorigenesis. The latter is evident as inheritance of mutations ... ...

    Abstract An important role for the DNA mismatch repair (MMR) pathway in maintaining genomic stability is embodied in its conservation through evolution and the link between loss of MMR function and tumorigenesis. The latter is evident as inheritance of mutations within the major MMR genes give rise to the cancer predisposition condition, Lynch syndrome. Nonetheless, how MMR loss contributes to tumorigenesis is not completely understood. In addition to preventing the accumulation of mutations, MMR also directs cellular responses, such as cell cycle checkpoint or apoptosis activation, to different forms of DNA damage. Understanding this MMR-dependent DNA damage response may provide insight into the full tumor suppressing capabilities of the MMR pathway. Here, we delve into the proposed mechanisms for the MMR-dependent response to DNA damaging agents. We discuss how these pre-clinical findings extend to the clinical treatment of cancers, emphasizing MMR status as a crucial variable in selection of chemotherapeutic regimens. Also, we discuss how loss of the MMR-dependent damage response could promote tumorigenesis via the establishment of a survival advantage to endogenous levels of stress in MMR-deficient cells.
    MeSH term(s) DNA Damage ; DNA Mismatch Repair/genetics ; DNA-Directed DNA Polymerase/metabolism ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics
    Chemical Substances DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2019-04-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2019.03.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Mismatch repair defects and Lynch syndrome: The role of the basic scientist in the battle against cancer.

    Heinen, Christopher D

    DNA repair

    2015  Volume 38, Page(s) 127–134

    Abstract: We have currently entered a genomic era of cancer research which may soon lead to a genomic era of cancer treatment. Patient DNA sequencing information may lead to a personalized approach to managing an individual's cancer as well as future cancer risk. ... ...

    Abstract We have currently entered a genomic era of cancer research which may soon lead to a genomic era of cancer treatment. Patient DNA sequencing information may lead to a personalized approach to managing an individual's cancer as well as future cancer risk. The success of this approach, however, begins not necessarily in the clinician's office, but rather at the laboratory bench of the basic scientist. The basic scientist plays a critical role since the DNA sequencing information is of limited use unless one knows the function of the gene that is altered and the manner by which a sequence alteration affects that function. The role of basic science research in aiding the clinical management of a disease is perhaps best exemplified by considering the case of Lynch syndrome, a hereditary disease that predisposes patients to colorectal and other cancers. This review will examine how the diagnosis, treatment and even prevention of Lynch syndrome-associated cancers has benefitted from extensive basic science research on the DNA mismatch repair genes whose alteration underlies this condition.
    MeSH term(s) Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Mismatch Repair ; Genes, Neoplasm ; Humans ; Mutation/genetics
    Language English
    Publishing date 2015-12-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2015.11.025
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Loss of mismatch repair promotes a direct selective advantage in human stem cells.

    Madden-Hennessey, Kirby / Gupta, Dipika / Radecki, Alexander A / Guild, Caroline / Rath, Abhijit / Heinen, Christopher D

    Stem cell reports

    2022  Volume 17, Issue 12, Page(s) 2661–2673

    Abstract: Lynch syndrome (LS) is the most common hereditary form of colon cancer, resulting from a germline mutation in a DNA mismatch repair (MMR) gene. Loss of MMR in cells establishes a mutator phenotype, which may underlie its link to cancer. Acquired ... ...

    Abstract Lynch syndrome (LS) is the most common hereditary form of colon cancer, resulting from a germline mutation in a DNA mismatch repair (MMR) gene. Loss of MMR in cells establishes a mutator phenotype, which may underlie its link to cancer. Acquired downstream mutations that provide the cell a selective advantage would contribute to tumorigenesis. It is unclear, however, whether loss of MMR has other consequences that would directly result in a selective advantage. We found that knockout of the MMR gene MSH2 results in an immediate survival advantage in human stem cells grown under standard cell culture conditions. This advantage results, in part, from an MMR-dependent response to oxidative stress. We also found that loss of MMR gives rise to enhanced formation and growth of human colonic organoids. These results suggest that loss of MMR may affect cells in ways beyond just increasing mutation frequency that could influence tumorigenesis.
    MeSH term(s) Humans ; DNA Mismatch Repair ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Germ-Line Mutation ; Stem Cells ; Carcinogenesis
    Language English
    Publishing date 2022-11-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2022.10.009
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  4. Article ; Online: Translating mismatch repair mechanism into cancer care.

    Heinen, Christopher D

    Current drug targets

    2014  Volume 15, Issue 1, Page(s) 53–64

    Abstract: The first DNA mismatch repair gene was identified in Escherichia coli nearly fifty years ago. Since then, five decades of basic biomedical research on this important repair pathway have led to an extensive understanding of its molecular mechanism. The ... ...

    Abstract The first DNA mismatch repair gene was identified in Escherichia coli nearly fifty years ago. Since then, five decades of basic biomedical research on this important repair pathway have led to an extensive understanding of its molecular mechanism. The significance of this work was clearly highlighted in the early 1990's when mutations in the human homologs of the mismatch repair genes were identified as responsible for Lynch syndrome (also known as hereditary non-polyposis colon cancer), the most common form of hereditary colorectal cancer. Basic science research on mismatch repair in lower organisms directly led researchers to the discovery of this link between defective mismatch repair and cancer and continues to guide clinical decisions today. The knowledge that disrupted mismatch repair function gives rise to the nucleotide-level form of genomic instability called microsatellite instability continues to be an important diagnostic tool for identifying Lynch syndrome patients as well as sporadic cancer patients who suffer from mismatch repairdefective cancers. Today, clinicians are using the information about mismatch repair molecular mechanism to guide decisions about cancer therapy as well to devise new therapies. In this review, we will examine what is known about the molecular function of the human mismatch repair pathway. We will highlight how this information is being used in cancer diagnosis and treatment. We will also discuss strategies being designed to target the 10-15% of colorectal, endometrial, ovarian and other cancers with defective mismatch repair.
    MeSH term(s) Base Pair Mismatch ; DNA Repair ; Humans ; Neoplasms/therapy
    Language English
    Publishing date 2014-01-04
    Publishing country United Arab Emirates
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2064859-5
    ISSN 1873-5592 ; 1389-4501
    ISSN (online) 1873-5592
    ISSN 1389-4501
    DOI 10.2174/1389450114666140106100128
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Enhanced gene targeting to evaluate Lynch syndrome alterations.

    Fishel, Richard / Heinen, Christopher D

    Proceedings of the National Academy of Sciences of the United States of America

    2016  Volume 113, Issue 15, Page(s) 3918–3920

    MeSH term(s) Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Gene Targeting ; Germ-Line Mutation ; Humans ; MutS Homolog 2 Protein/genetics
    Chemical Substances MutS Homolog 2 Protein (EC 3.6.1.3)
    Language English
    Publishing date 2016-04-12
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1602650113
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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  6. Article ; Online: Functional and phenotypic consequences of an unusual inversion in MSH2.

    Pelletier, Dylan / Rath, Abhijit / Sabbaghian, Nelly / Pelmus, Manuela / Hudon, Catherine / Jacob, Karine / Witowski, Leora / Saskin, Avi / Heinen, Christopher D / Foulkes, William D

    Familial cancer

    2023  Volume 23, Issue 1, Page(s) 1–7

    Abstract: Lynch syndrome is an autosomal dominant disorder that usually results from a pathogenic germline variant in one of four genes (MSH2, MSH6, MLH1, PMS2) involved in DNA mismatch repair. Carriers of such variants are at risk of developing numerous cancers ... ...

    Abstract Lynch syndrome is an autosomal dominant disorder that usually results from a pathogenic germline variant in one of four genes (MSH2, MSH6, MLH1, PMS2) involved in DNA mismatch repair. Carriers of such variants are at risk of developing numerous cancers during adulthood. Here we report on a family suspected of having Lynch syndrome due to a history of endometrial adenocarcinoma, ovarian clear cell carcinoma, and adenocarcinoma of the duodenum in whom we identified a germline 29 nucleotide in-frame inversion in exon 3 of MSH2. We further show that this variant is almost completely absent at the protein level, and that the associated cancers have complete loss of MSH2 and MSH6 expression by immunohistochemistry. Functional investigation of this inversion in a laboratory setting revealed a resultant abnormal protein function. Thus, we have identified an unusual, small germline inversion in a mismatch repair gene that does not lead to a premature stop codon yet appears likely to be causal for the observed cancers.
    MeSH term(s) Humans ; Adult ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology ; MutS Homolog 2 Protein/genetics ; MutS Homolog 2 Protein/metabolism ; Germ-Line Mutation ; Adenocarcinoma/genetics ; Exons ; DNA Mismatch Repair/genetics ; MutL Protein Homolog 1/genetics ; Mismatch Repair Endonuclease PMS2/genetics ; Mismatch Repair Endonuclease PMS2/metabolism
    Chemical Substances MutS Homolog 2 Protein (EC 3.6.1.3) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; MSH2 protein, human (EC 3.6.1.3)
    Language English
    Publishing date 2023-11-14
    Publishing country Netherlands
    Document type Letter
    ZDB-ID 1502496-9
    ISSN 1573-7292 ; 1389-9600
    ISSN (online) 1573-7292
    ISSN 1389-9600
    DOI 10.1007/s10689-023-00350-3
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    Zs.A 6099: Show issues Location:
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  7. Article: Genotype to phenotype: analyzing the effects of inherited mutations in colorectal cancer families.

    Heinen, Christopher D

    Mutation research

    2009  Volume 693, Issue 1-2, Page(s) 32–45

    Abstract: With improvements to DNA sequencing technologies, including the advent of massively parallel sequencing to perform "deep sequencing" of tissue samples, the ability to determine all of the nucleotide variations in a tumor becomes a possibility. This ... ...

    Abstract With improvements to DNA sequencing technologies, including the advent of massively parallel sequencing to perform "deep sequencing" of tissue samples, the ability to determine all of the nucleotide variations in a tumor becomes a possibility. This information will allow us to more fully understand the heterogeneity within each tumor, as well as to identify novel genes involved in cancer development. However, the new challenge that arises will be to interpret the pathogenic significance of each genetic variant. The enormity and complexity of this challenge can be demonstrated by focusing on just the genes involved in the hereditary colon cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis coli (HNPCC). The genes responsible for each disease were identified almost two decades ago -APC for FAP and the MMR genes for HNPCC - and a large number of germline variations have been identified in these genes in hereditary cancer patients. However, relating the effect of an individual genotype to phenotype is not always straightforward. This review focuses on the roles of the APC and MMR genes in tumor development and the work that has been done to relate different variants in each gene to functional aberrations and ultimately tumorigenesis. By considering the work that has already been done on two well-defined diseases with clear genetic associations, one can begin to understand the challenges that lie ahead as new genes and gene mutations are discovered through tumor sequencing.
    MeSH term(s) Adenomatous Polyposis Coli/genetics ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Mismatch Repair/genetics ; Genes, APC ; Genetic Variation ; Genotype ; Humans ; Mutation ; Phenotype
    Language English
    Publishing date 2009-09-17
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 206607-5
    ISSN 1873-135X ; 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    ISSN (online) 1873-135X
    ISSN 0027-5107 ; 1383-5718 ; 0165-1110 ; 0165-1161 ; 0165-7992 ; 0921-8777 ; 0165-1218 ; 1383-5726 ; 0167-8817 ; 0921-8734 ; 1383-5742
    DOI 10.1016/j.mrfmmm.2009.09.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage.

    Gupta, Dipika / Lin, Bo / Cowan, Ann / Heinen, Christopher D

    Proceedings of the National Academy of Sciences of the United States of America

    2018  Volume 115, Issue 7, Page(s) 1523–1528

    Abstract: The mismatch repair pathway (MMR) is essential for removing DNA polymerase errors, thereby maintaining genomic stability. Loss of MMR function increases mutation frequency and is associated with tumorigenesis. However, how MMR is executed at active DNA ... ...

    Abstract The mismatch repair pathway (MMR) is essential for removing DNA polymerase errors, thereby maintaining genomic stability. Loss of MMR function increases mutation frequency and is associated with tumorigenesis. However, how MMR is executed at active DNA replication forks is unclear. This has important implications for understanding how MMR repairs
    MeSH term(s) Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Checkpoint Kinase 1/genetics ; Checkpoint Kinase 1/metabolism ; DNA Damage/physiology ; DNA Mismatch Repair/physiology ; DNA Replication ; Embryonic Stem Cells/drug effects ; Embryonic Stem Cells/physiology ; Enzyme Activation ; HeLa Cells ; Humans ; Methylnitronitrosoguanidine/pharmacology ; MutS Homolog 2 Protein/genetics ; MutS Homolog 2 Protein/metabolism ; S Phase/physiology
    Chemical Substances Methylnitronitrosoguanidine (12H3O2UGSF) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; MSH2 protein, human (EC 3.6.1.3) ; MutS Homolog 2 Protein (EC 3.6.1.3)
    Language English
    Publishing date 2018-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1720355115
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  9. Article ; Online: A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.

    Rath, Abhijit / Radecki, Alexander A / Rahman, Kaussar / Gilmore, Rachel B / Hudson, Jonathan R / Cenci, Matthew / Tavtigian, Sean V / Grady, James P / Heinen, Christopher D

    Human mutation

    2022  Volume 43, Issue 12, Page(s) 2295–2307

    Abstract: Functional assays provide important evidence for classifying the disease significance of germline variants in DNA mismatch repair genes. Numerous laboratories, including our own, have developed functional assays to study mismatch repair gene variants. ... ...

    Abstract Functional assays provide important evidence for classifying the disease significance of germline variants in DNA mismatch repair genes. Numerous laboratories, including our own, have developed functional assays to study mismatch repair gene variants. However, previous assays are limited due to the model system employed, the manner of gene expression, or the environment in which function is assessed. Here, we developed a human cell-based approach for testing the function of variants of uncertain significance (VUS) in the MLH1 gene. Using clustered regularly interspaced short palindromic repeats gene editing, we knocked in MLH1 VUS into the endogenous MLH1 loci in human embryonic stem cells. We examined their impact on RNA and protein, including their ability to prevent microsatellite instability and instigate a DNA damage response. A statistical clustering analysis determined the range of functions associated with known pathogenic or benign variants, and linear regression was performed using existing odds in favor of pathogenicity scores for these control variants to calibrate our functional assay results. By converting the functional outputs into a single odds in favor of pathogenicity score, variant classification expert panels can use these results to readily reassess these VUS. Ultimately, this information will guide proper diagnosis and disease management for suspected Lynch syndrome patients.
    MeSH term(s) Humans ; DNA Mismatch Repair/genetics ; MutL Protein Homolog 1/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology ; Microsatellite Instability ; Germ-Line Mutation/genetics ; Mismatch Repair Endonuclease PMS2/genetics
    Chemical Substances MutL Protein Homolog 1 (EC 3.6.1.3) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; MLH1 protein, human
    Language English
    Publishing date 2022-09-12
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1126646-6
    ISSN 1098-1004 ; 1059-7794
    ISSN (online) 1098-1004
    ISSN 1059-7794
    DOI 10.1002/humu.24462
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3586: Show issues Location:
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  10. Article ; Online: Human pluripotent stem cells have a novel mismatch repair-dependent damage response.

    Lin, Bo / Gupta, Dipika / Heinen, Christopher D

    The Journal of biological chemistry

    2014  Volume 289, Issue 35, Page(s) 24314–24324

    Abstract: Human pluripotent stem cells (PSCs) are presumed to have robust DNA repair pathways to ensure genome stability. PSCs likely need to protect against mutations that would otherwise be propagated throughout all tissues of the developing embryo. How these ... ...

    Abstract Human pluripotent stem cells (PSCs) are presumed to have robust DNA repair pathways to ensure genome stability. PSCs likely need to protect against mutations that would otherwise be propagated throughout all tissues of the developing embryo. How these cells respond to genotoxic stress has only recently begun to be investigated. Although PSCs appear to respond to certain forms of damage more efficiently than somatic cells, some DNA damage response pathways such as the replication stress response may be lacking. Not all DNA repair pathways, including the DNA mismatch repair (MMR) pathway, have been well characterized in PSCs to date. MMR maintains genomic stability by repairing DNA polymerase errors. MMR is also involved in the induction of cell cycle arrest and apoptosis in response to certain exogenous DNA-damaging agents. Here, we examined MMR function in PSCs. We have demonstrated that PSCs contain a robust MMR pathway and are highly sensitive to DNA alkylation damage in an MMR-dependent manner. Interestingly, the nature of this alkylation response differs from that previously reported in somatic cell types. In somatic cells, a permanent G2/M cell cycle arrest is induced in the second cell cycle after DNA damage. The PSCs, however, directly undergo apoptosis in the first cell cycle. This response reveals that PSCs rely on apoptotic cell death as an important defense to avoid mutation accumulation. Our results also suggest an alternative molecular mechanism by which the MMR pathway can induce a response to DNA damage that may have implications for tumorigenesis.
    MeSH term(s) Apoptosis/drug effects ; Base Pair Mismatch ; Cell Cycle/drug effects ; Cells, Cultured ; DNA Damage ; DNA Repair ; Humans ; Induced Pluripotent Stem Cells/cytology ; Methylnitronitrosoguanidine/pharmacology
    Chemical Substances Methylnitronitrosoguanidine (12H3O2UGSF)
    Language English
    Publishing date 2014-07-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M114.570937
    Database MEDical Literature Analysis and Retrieval System OnLINE

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