TP53-dependent chromosome instability is associated with transient reductions in telomere length in immortal telomerase-positive cell lines

Telomere shortening in telomerase-negative somatic cells leads to the activ ation of the TP53 protein and the elimination of potentially unstable cells . We examined the effect of TP53 gene expression on both telomere metabolis m and chromosome stability in immortal, telomerase-positive cell lines. Tel omere length, telomerase activity, and chromosome instability were measured in multiple clones isolated from three related human B-lymphoblast cell li nes that vary in TP53 expression; TK6 cells express wild-type TP53, WTKI ce lls overexpress a mutant form of TP53, and NH32 cells express no TP53 prote in. Clonal variations in both telomere length and chromosome stability were observed, and shorter telomeres were associated with higher levels of chro mosome instability. The shortest telomeres were found in WTKI- and NH32-der ived cells, and these cells had 5- to 10-fold higher levels of chromosome i nstability. The primary marker of instability was the presence of dicentric chromosomes. Aneuploidy and other stable chromosome alterations were also found in clones showing high levels of dicentrics. Polyploidy was found onl y in WTKI-derived cells. Both telomere length and chromosome instability fl uctuated in the different cell populations with time in culture, presumably as unstable cells and cells with short telomeres were eliminated from the growing population. Our results suggest that transient reductions in telome re lengths may be common in immortal cell lines and that these alterations in telomere metabolism can have a profound effect on chromosome stability. (C) 2001 Wiley-Liss. Inc.