Abstract
Tankyrase1 is a multifunctional poly(ADP-ribose) polymerase that can localize to telomeres through its interaction with the shelterin component TRF1. Tankyrase1 poly(ADP-ribosyl)ates TRF1 in vitro, and its nuclear overexpression leads to loss of TRF1 and telomere elongation, suggesting that tankyrase1 is a positive regulator of telomere length. In agreement with this proposal, we show that tankyrase1 RNA interference results in telomere shortening proportional to the level of knockdown. Furthermore, we show that a tankyrase1-resistant form of TRF1 enforced normal telomere length control, indicating that tankyrase1 is not required downstream of TRF1 in this pathway. Thus, in human cells, tankyrase1 appears to act upstream of TRF1, promoting telomere elongation through the removal of TRF1. This pathway appears absent from mouse cells. We show that murine TRF1, which lacks the canonical tankyrase1-binding site, is not a substrate for tankyrase1 poly(ADP-ribosyl)sylation in vitro. Furthermore, overexpression of tankyrase1 in mouse nuclei did not remove TRF1 from telomeres and had no detectable effect on other components of mouse shelterin. We propose that the tankyrase1-controlled telomere extension is a human-specific elaboration that allows additional control over telomere length in telomerase positive cells.
Highlights
POT1, TPP1, TIN2, and Rap1) whose abundance at chromosome ends is dictated by the length of the duplex telomeric repeat array
Telomere healing experiments demonstrated that cells have the ability to monitor and regulate telomerase at individual telomeres, and tethering of TRF1 at subtelomeric sites showed that TRF1 can modulate telomere length in cis
When TIN2 is inhibited in vivo, TRF1 appears more sensitive to the endogenous tankyrase1, and telomere elongation occurs
Summary
POT1, TPP1, TIN2, and Rap1) whose abundance at chromosome ends is dictated by the length of the duplex telomeric repeat array. Inhibition of TRF1, TPP1, TIN2, and POT1 results in telomere elongation, whereas overexpression of several shelterin components shortens the length of the telomeres. The blots were tankyrase1 have largely failed to yield the expected telomere probed overnight at 4 °C with 35S-labeled in vitro translated shortening phenotypes [15, 17], success with one protein prepared using the TNT T7-coupled reticulocyte lysate allele has been reported [16].
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