Control of human telomere length by TRF1 and TRF2

Telomere length in human cells is controlled by a homeostasis mechanism tha t involves telomerase and the negative regulator of telomere length, TRF1 ( ITAGGG repeat binding factor 1). Here we report that TRF2, a TRF1-related p rotein previously implicated in protection of chromosome ends, is a second negative regulator of telomere length, Overexpression of TRF2 results in th e progressive shortening of telomere length, similar to the phenotype obser ved with TRF1. However, while induction of TRF1 could be maintained over mo re than 300 population doublings and resulted in stable, short telomeres, t he expression of exogenous TRF2 was extinguished and the telomeres eventual ly regained their original length. Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and T RF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts. Neither TRF1 nor TRF2 affected the express ion level of telomerase. Furthermore, the presence of TRF1 or TRF2 on a sho rt linear telomerase substrate did not inhibit the enzymatic activity of te lomerase in vitro. These findings are consistent with the recently proposed t loop model of telomere length homeostasis in which telomerase-dependent telomere elongation is blocked by sequestration of the 3' telomere terminus in TRF1- and TRF2-induced telomeric loops.