Mismatch Repair (MMR) is an evolutionary conserved system that targets polymerase mistakes for repair on the newly synthesized DNA strand. Based on bacteria and yeast studies, there appears to be specific recognition patterns by components of DNA MMR, although data on human repair is lacking. In addition to single base pair mismatches that distort the DNA strand, DNA MMR can detect """"""""loops"""""""" formed at repetitive sequences termed microsatellites, presumably caused by slippage by the DNA polymerase that leaves at least one extra nucleotide on a DNA strand. The result is a frameshift mutation at the microsatellite, which can be detected electrophoretically. Most microsatellites are in non-coding regions of DNA, but certain tumor suppressor genes contain coding microsatellites that develop frameshift mutations when DNA MMR is impaired. Mutations of PTEN, TGFBR2, ACVR2, and BAX are often found in cancers from patients with Lynch syndrome (caused by germline mutation of a DNA MMR gene), or in sporadic microsatellite unstable colorectal cancers. In this proposal, our overall hypothesis is that the human DNA mismatch repair system has specific recognition fidelity in targeting repair of frameshifted loops. We propose based on the individual defect of the DNA mismatch repair system that non-coding microsatellites will be repaired at varied rates. Similarly, coding microsatellites found in target genes that help determine the enhanced growth of microsatellite unstable cancers will become mutated at varying rates based on the type of mismatch repair defect. We hypothesize that in addition to a specific mismatch repair defect, the surrounding DNA structure may influence the ease or ability of a coding microsatellite to become mutated. The studies proposed here are designed to help understand why and how target genes become mutated in microsatellite unstable cancer. These studies are important to understanding the pathogenesis of microsatellite unstable colorectal cancer, and may provide clues to a mechanism for interrupting the mutation process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067287-03
Application #
7277826
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
2005-09-01
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$292,988
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Koi, Minoru; Okita, Yoshiki; Carethers, John M (2018) Fusobacterium nucleatum Infection in Colorectal Cancer: Linking Inflammation, DNA Mismatch Repair and Genetic and Epigenetic Alterations. J Anus Rectum Colon 2:37-46
Koi, Minoru; Tseng-Rogenski, Stephanie S; Carethers, John M (2018) Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer. World J Gastrointest Oncol 10:1-14
Carethers, John M (2017) Microsatellite Instability Pathway and EMAST in Colorectal Cancer. Curr Colorectal Cancer Rep 13:73-80
Ashktorab, Hassan; Kupfer, Sonia S; Brim, Hassan et al. (2017) Racial Disparity in Gastrointestinal Cancer Risk. Gastroenterology 153:910-923
Basa, Ranor C B; Davies, Vince; Li, Xiaoxiao et al. (2016) Decreased Anti-Tumor Cytotoxic Immunity among Microsatellite-Stable Colon Cancers from African Americans. PLoS One 11:e0156660
Carethers, John M; Goel, Ajay (2016) Presentation of the Julius M. Friedenwald Medal to C. Richard Boland, MD, AGAF. Gastroenterology 150:1673-1677
Carethers, John M (2016) HEREDITARY, SPORADIC AND METASTATIC COLORECTAL CANCER ARE COMMONLY DRIVEN BY SPECIFIC SPECTRUMS OF DEFECTIVE DNA MISMATCH REPAIR COMPONENTS. Trans Am Clin Climatol Assoc 127:81-97
Carethers, John M (2016) Facilitating Minority Medical Education, Research, and Faculty. Dig Dis Sci 61:1436-9
Koi, Minoru; Garcia, Melissa; Choi, Chan et al. (2016) Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis. Gastroenterology 150:944-55
Carethers, John M (2016) The Increasing Incidence of Colorectal Cancers Diagnosed in Subjects Under Age 50 Among Races: CRaCking the Conundrum. Dig Dis Sci 61:2767-2769

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