DISSOCIATION OF TELOMERE DYNAMICS FROM TELOMERASE ACTIVITY IN HUMAN THYROID-CANCER CELLS

Prevention of telomere erosion through acquisition of telomerase activ ity is thought to be an essential mechanism in most human cancer cells for avoidance of cellular senescence and crisis. It has been generall y assumed that once telomerase has been activated, no further telomere shortening should ensue. We show here, however, that a much more comp lex pattern of telomere dynamics can exist in telomerase-positive immo rtal cancer cells. Using a panel of subclones derived from a human thy roid cancer cell line, K1E7, we found that some clones show persistent decline in mean telomere restriction fragment (TRF) length by up to 2 kb over 450 population doublings (pd), despite sustained high telomer ase activity (as assessed by the in vitro ''TRAP'' assay). TRF length subsequently stabilized at around 5 kb, but with no corresponding incr ease in telomerase activity. One clone showed an even more unexpected biphasic time course, with the mean TRF length initially increasing by 1.5 kb over 90 pd, before ''plateauing'' and then returning over a si milar period to its original value, again without any correlation to T RAP activity. Such dissociations between telomere dynamics and telomer ase activity support the existence of additional controls on telomere length in the intact cell. Our observations are consistent with curren t negative-feedback models of telomere length regulation by telomere b inding proteins and these cell lines should prove useful experimental tools for their further evaluation. (C) 1998 Academic Press.