Telomere Maintenance in the Absence of Telomerase

摘要

Telomere maintenance is critical to oncogenesis. Therefore, understanding both telomerase-dependent and telomerase-independent pathways of maintenance will be important for therapeutic strategies. In the budding yeasts S. cerevisiae and K. lactis, telomerase- independent survival is mediated via RAD52-dependent recombination which results in amplification of telomeric and subtelomeric repeat sequences. Since these repeat sequences are not identical, the mismatch repair pathway (MMR) could potentially block recombination between such homeologous sequences. We have shown that mutations in the MMR genes MSH2, MLHJ, or PMSl, as well as double mutations in MSH3 and MSH6, enhance telomerase- independent survival in S. cerevisiae in a RAD52-dependent manner. The MMR effect is not a general mutator effect, as a proofreading defective POL3 does not enhance telomerase-independent survival. Preliminary results also show that disrupting MSH2 in K. lactis enhances telomerase-independent survival, albeit to a lesser extent than in % cerevisiae. This is consistent with the much larger number of potential mismatches in S.cerevisae compared to K. lactis telomeres, which are more similar to human telomeres. These results suggest the possibility that enhanced telomeric recombination in human cells with MMR defects may contribute to cell immortalization in the absence of telomerase reactivation.