Telomerase can inhibit the recombination-based pathway of telomere maintenance in human cells

Telomere length can be maintained by telomerase or by a recombination-based pathway. Because individual telomeres in cells using the recombination-bas ed pathway of telomere maintenance appear to periodically become extremely short, cells using this pathway to maintain telomeres may be faced with a c ontinuous state of crisis. We expressed telomerase in a human cell line tha t uses the recombination-based pathway of telomere maintenance to test whet her telomerase would prevent telomeres from becoming critically short and e xamine the effects that this might have on the recombination-based pathway of telomere maintenance. In these. cells, telomerase maintains the length o f the shortest telomeres. In some cases, the long heterogeneous telomeres a re completely lost, and the cells now permanently contain short telomeres a fter only 40 population doublings. This corresponds to a telomere reduction rate of 500 base pairs/population doubling, a rate that is much faster tha n expected for normal telomere shortening but is consistent with the rapid telomere deletion events observed in cells using the recombination-based. p athway of telomere maintenance (Murnane, J. P., Sabatier, L., Marder, B. A. , and Morgan, W. F. (1994) EMBO J. 13, 4953-4962). We also observed reducti ons in the fraction of cells containing alternative lengthening of telomere -associated promyelocytic leukemia bodies and extrachromosomal telomere rep eats; however, no alterations in the rate of sister chromatid exchange were observed. Our results demonstrate that human cells using the recombination -based pathway of telomere maintenance retain factors required for telomera se to maintain telomeres and that once the telomerase-based pathway of telo mere length regulation is engaged, recombination-based elongation of telome res can be functionally inhibited.