Nature Genetics36, 618 - 623 (2004)
Published online: 9 May 2004; | doi:10.1038/ng1360
TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex
Jeffrey Zheng-Sheng Ye1, 2, 3
& Titia de Lange1
1
The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
2
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
3
Present Address: Division of Hematology, Department of Medicine and Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Telomere length in humans is partly controlled by a feedback mechanism in which telomere elongation by telomerase is limited by the accumulation of the TRF1 complex at chromosome ends1,
2,
3,
4,
5. TRF1 itself can be inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its interacting partner tankyrase 1, which abolishes its DNA binding activity in vitro and removes the TRF1 complex from telomeres in vivo. Here we report that the inhibition of TRF1 by tankyrase is in turn controlled by a second TRF1-interacting factor, TIN2 (ref. 6). Partial knockdown of TIN2 by small hairpin RNA in a telomerase-positive cell line resulted in telomere elongation, which is typical of reduced TRF1 function. Transient inhibition of TIN2 with small interfering RNA led to diminished telomeric TRF1 signals. This effect could be reversed with the PARP inhibitor 3-aminobenzamide and did not occur in cells overexpressing a PARP-dead mutant of tankyrase 1. TIN2 formed a ternary complex with TRF1 and tankyrase 1 and stabilized their interaction, an effect also observed with the PARP-dead mutant of tankyrase 1. In vitro, TIN2 protected TRF1 from poly(ADP-ribosyl)ation by tankyrase 1 without affecting tankyrase 1 automodification. These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length.
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