Telomere elongation by a mutant tankyrase 1 without TRF1 poly(ADP-ribosyl)ation.
Telomeres are the capping structures of the eukaryotic chromosome ends. Tankyrase 1 is a poly(ADP-ribose) polymerase that elongates telomeres in a telomerase-dependent manner. This function of tankyrase 1 is mediated by down-regulation of TRF1, a negative regulator of telomere access to telomerase. Namely, tankyrase 1 poly(ADP-ribosyl)ates (PARsylates) TRF1, which in turn dissociates TRF1 from telomeres. The resulting telomeres become better substrates for telomerase-mediated DNA extension. Tankyrase 1 has five independent TRF1 binding sites, ARC (ANK repeat cluster) I to V. Among them, the most C-terminal ARC V is required for TRF1 PARsylation and its release from telomeres. By contrast, functional significance of other four ARCs remains elusive. In this study, we generated a mutant tankyrase 1 that had inactive ARC IV and lacked ARC V but elongated telomeres without TRF1 PARsylation. Consistent with the failure in PARsylation, this mutant only marginally released TRF1 from telomeres. Still, it decreased telomere binding of POT1, a downstream effector of TRF1-mediated telomere length control, and elongated the telomeric 3'-overhang as the wild-type tankyrase 1 did. Thus even without TRF1 PARsylation, this mutant tankyrase 1 seemed to loosen the closed structure of the telomeric heterochromatin. These findings suggest a new role for multiple ARCs in telomere extension by tankyrase 1.
Muramatsu
Yukiko
Y
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Tahara
Hidetoshi
H
Ono
Taeko
T
Tsuruo
Takashi
T
Seimiya
Hiroyuki
H
D001665:Binding Sites; D006367:HeLa Cells; D006801:Humans; D050505:Mutant Proteins; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000089804:Shelterin Complex; D038501:Tankyrases / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism*; D014162:Transfection
D050505:Mutant Proteins; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D011064:Poly Adenosine Diphosphate Ribose; D038501:Tankyrases