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The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome

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Abstract

The majority of Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), has been linked to heterozygous defects in DNA mismatch repair (MMR). MMR is a highly conserved pathway that recognizes and repairs polymerase misincorporation errors and nucleotide damage as well as functioning as a damage sensor that signals apoptosis. Loss-of-heterozygosity (LOH) that retains the mutant MMR allele and epigenetic silencing of MMR genes are associated with an increased mutation rate that drives carcinogenesis as well as microsatellite instability that is a hallmark of LS/HNPCC. Understanding the biophysical functions of the MMR components is crucial to elucidating the role of MMR in human tumorigenesis and determining the pathogenetic consequences of patients that present in the clinic with an uncharacterized variant of the MMR genes. We summarize the historical association between LS/HNPCC and MMR, discuss the mechanism of the MMR and finally examine the functional analysis of MMR defects found in LS/HNPCC patients and their relationship with the severity of the disease.

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Acknowledgments

The authors would like to thank Christopher Heinen and members of the Fishel Laboratory for helpful discussions. This work was supported by NIH Grant CA67007.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA

    Juana V. Martín-López & Richard Fishel

  2. Physics Department, The Ohio State University, Columbus, OH, 43210, USA

    Richard Fishel

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Martín-López, J.V., Fishel, R. The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome. Familial Cancer 12, 159–168 (2013). https://doi.org/10.1007/s10689-013-9635-x

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