Defects in mismatch repair promote telomerase-independent proliferation

Nature. 2001 Jun 7;411(6838):713-6. doi: 10.1038/35079641.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Pair Mismatch / genetics
  • Cell Division*
  • Cell Transformation, Neoplastic / genetics
  • Chromosomes, Fungal
  • Cloning, Molecular
  • DNA Repair*
  • DNA-Binding Proteins
  • Fungal Proteins
  • Humans
  • Kluyveromyces / genetics
  • Molecular Sequence Data
  • MutS Homolog 2 Protein
  • Mutation
  • Recombination, Genetic
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins*
  • Telomerase / metabolism*
  • Telomere

Substances

  • DNA-Binding Proteins
  • Fungal Proteins
  • Saccharomyces cerevisiae Proteins
  • Telomerase
  • MSH2 protein, S cerevisiae
  • MutS Homolog 2 Protein

Associated data

  • GENBANK/AF332582