title: Deficiency in DNA mismatch repair increases the rate of telomere shortening in normal human cells.
abstract: DNA mismatch repair (MMR) is essential for genome stability and inheritance of a mutated MMR gene, most frequently MSH2 or MLH1, results in cancer predisposition known as Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). Tumors that arise through MMR deficiency show instability at simple tandem repeat loci (STRs) throughout the genome, known as microsatellite instability (MSI). The STR instability is dominated by errors that accumulate during replication in the absence of effective MMR. In this study we show that there is a high level of instability within telomeric DNA with a tendency toward deletions in tumor-derived MMR defective cell lines. We downregulated MSH2 expression in a normal fibroblast cell line and isolated four clones, with differing levels of MSH2 depletion. The telomere-shortening rate was measured at the Xp/Yp, 12q, and 17p telomeres in the MSH2 depleted and three control clones. Interestingly the mean telomere-shortening rate in the clones with MSH2 depletion was significantly greater than in the control clones. This is the first demonstration that MSH2 deficiency alone can lead to accelerated telomere shortening in normal human cells.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Aaron
authors.initials: A
authors.lastname: Mendez-Bermudez
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Royle
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D053842:Microsatellite Instability; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein / Q000172:deficiency / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein