A yeast two-hybrid screen using human TRF1 as bait identified tankyrase, a 142 kDa protein with homology to ankyrins and to the catalytic domain of poly(ADP-ribose)

Telomeres function to ensure the complete replication of chromosome ends, a task which can not be accomplished by conventional DNA polymerases. Telomeres are maintained by telomerase, a reverse transcriptase that adds TTAGGG repeats onto the 3′ ends of vertebrate chromosomes (Greider and Blackburn, 1985; reviewed by Nugent and Lundblad, 1998). Cells have mechanisms to monitor telomere length and to ensure that telomeric repeats are added to chromosome ends in a controlled fashion (reviewed by Shore, 1997). Human telomere function requires two telomere specific DNA binding proteins, TTAGGG repeat binding factors, TRF1 and TRF2 (Bilaud et al., 1997; Broccoli et al., 1997; Chong et al., 1995; reviewed by Smith and de Lange, 1997). TRF1 functions as a negative regulator of telomere length maintenance (van Steensel and de Lange, 1997). Long-term overexpression of TRF1 in a telomerase-positive tumor cell line results in progressive telomere shortening, whereas inhibition of TRF1 induces telomere elongation (van Steensel and de Lange, 1997). TRF1 does not control the expression of telomerase itself, but is thought to act in cis by inhibiting the action of telomerase at individual telomere termini. The mechanism by which TRF1 controls telomere synthesis by telomerase is unclear, but in vitro studies indicate that it is likely to involve additional proteins (A. Smogorzewska et al., unpublished). A yeast two-hybrid screen using human TRF1 as bait identified tankyrase, a 142 kDa protein with homology to ankyrins and to the catalytic domain of poly(ADP-ribose) polymerase (PARP) (Smith et al., 1998). Tankyrase was found to co-localize with TRF1 to human telomeres indicating that it is a component of the human telomeric complex (Smith et al., 1998). Tankyrase is a new member of the ankyrin family, a group of structural proteins that link integral membrane proteins to the cytoskeleton (reviewed by Bennet, 1992). Like ankyrins, tankyrase contains 24 copies of the ANK repeat, a proteinprotein interacting motif, in a domain responsible for its interaction with TRF1 (Smith et al., 1998). Outside of the ankyrin domain there is no homology between tankyrase and the ankyrins. Instead, tankyrase contains in its carboxy terminus a region with homology to the catalytic domain of PARP. PARP is a nuclear enzyme that in response to DNA damage uses NAD+ to synthesize ADP-ribose polymers onto protein acceptors (reviewed by Jeggo, 1998; Lindahl et al., 1995). Poly(ADP-ribosyl)ation is a dramatic, short-lived posttranslational modification that is believed to function in the maintenance of genome integrity, although the molecular mechanism is unknown. Recombinant tankyrase was found to have PARP activity in vitro with both TRF1 and tankyrase 3649 Journal of Cell Science 112, 3649-3656 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0748