Mismatch repair has a central role in maintaining genomic stability by repa
iring DNA replication errors and inhibiting recombination between non-ident
ical (homeologous) sequences(1,2). Defects in mismatch repair have been lin
ked to certain human cancers, including hereditary non-polyposis colorectal
cancer (HNPCC) and sporadic tumours(3-5). A crucial requirement for tumour
cell proliferation is the maintenance of telomere length(6), and most tumo
urs achieve this by reactivating telomerase(7). In both yeast and human cel
ls, however, telomerase-independent telomere maintenance can occur as a res
ult of recombination-dependent exchanges between often imperfectly matched
telomeric sequences(8-12). Here we show that loss of mismatch-repair functi
on promotes cellular proliferation in the absence of telomerase. Defects in
mismatch repair, including mutations that correspond to the same amino-aci
d changes recovered from HNPCC tumours(13), 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 he
nce tumorigenesis.