ACCELERATED TELOMERE SHORTENING IN FLBROBLASTS AFTER EXTENDED PERIODSOF CONFLUENCY

Telomere length in MRC-5 fibroblasts remains constant if the cells are proliferation-inhibited for up to 3 months by confluency. However, th e apparent frequency of single-stranded sites in telomeres, measured a s sensitivity to degradation by S1 nuclease, increases about fourfold during this extended inhibition of proliferation. After release of the cells, the frequency of telomeric single-stranded sites decreases to control values, and the telomere shortening rate increases about three fold as compared to controls proliferating without inhibition. This ac celeration is transitory, the telomere shortening rate decreases to co ntrol values after about two population doublings after release. Final ly, temporarily arrested fibroblast populations senesce at a lower cum ulative population doubling level, but at about the same telomere leng th, as continuously proliferating controls. The data suggest that meta bolic time-dependent single strand degradation is a major cause of tel omere shortening. They support the idea that telomere shortening plays an important role in triggering cellular senescence. (C) 1998 Elsevie r Science Inc.