Defects in mismatch repair promote telomerase-independent proliferation.
Mismatch repair has a central role in maintaining genomic stability by repairing DNA replication errors and inhibiting recombination between non-identical (homeologous) sequences. Defects in mismatch repair have been linked to certain human cancers, including hereditary non-polyposis colorectal cancer (HNPCC) and sporadic tumours. A crucial requirement for tumour cell proliferation is the maintenance of telomere length, and most tumours achieve this by reactivating telomerase. In both yeast and human cells, however, telomerase-independent telomere maintenance can occur as a result of recombination-dependent exchanges between often imperfectly matched telomeric sequences. Here we show that loss of mismatch-repair function promotes cellular proliferation in the absence of telomerase. Defects in mismatch repair, including mutations that correspond to the same amino-acid changes recovered from HNPCC tumours, enhance telomerase-independent survival in both Saccharomyces cerevisiae and a related budding yeast with a degree of telomere sequence homology that is similar to human telomeres. These results indicate that enhanced telomeric recombination in human cells with mismatch-repair defects may contribute to cell immortalization and hence tumorigenesis.
Rizki
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Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lundblad
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D020137:Base Pair Mismatch / Q000235:genetics; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015825:Chromosomes, Fungal; D003001:Cloning, Molecular; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D006801:Humans; D007716:Kluyveromyces / Q000235:genetics; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D009154:Mutation; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein