Tankyrase promotes telomere elongation in human cells

Human telomeres are maintained by telomerase, a reverse transcriptase that adds telomeric repeats to chromosome ends [1,2], In human tumors and immort alized cells, telomeres are often maintained at a constant length setting [ 3,4], indicating that telomerase-mediated telomere elongation is tightly re gulated. Tankyrase, a telomeric poly(ADP-ribose) polymerase (PARP) [5], was identified through its interaction with TRF1 [6], a negative regulator of telomere extension by telomerase [7], Tankyrase-mediated ADP-ribosylation i nhibits binding of TRF1 to telomeric repeats in vitro [5], suggesting that tankyrase might regulate TRF1 and therefore control telomere dynamics in vi vo. Here, we present evidence that tankyrase acts as a positive regulator o f telomere elongation in vivo, apparently by inhibiting TRF1, Overexpressio n of tankyrase in the nucleus diminished the level of unmodified TRF1 in im munoblots and led to reduced immunofluorescence of TRF1 at interphase telom eres, Long-term overexpression of tankyrase in telomerase-positive human ce lls resulted in a gradual and progressive elongation of telomeres, A PARP-d eficient form of tankyrase failed to affect TRF1 and did not alter telomere length dynamics, consistent with ADP-ribosylation of TRF1 as the main caus e of altered telomere homeostasis. Our results indicate that tankyrase can induce telomere elongation in human cells. We propose that tankyrase-mediat ed ADP-ribosylation of TRF1 opens the telomeric complex, allowing access to telomerase.