title: Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes.
abstract: Telomeres are maintained by three DNA-binding proteins (telomeric repeat binding factor 1 [TRF1], TRF2, and protector of telomeres 1 [POT1]) and several associated factors. One factor, TRF1-interacting protein 2 (TIN2), binds TRF1 and TRF2 directly and POT1 indirectly. Along with two other proteins, TPP1 and hRap1, these form a soluble complex that may be the core telomere maintenance complex. It is not clear whether subcomplexes also exist in vivo. We provide evidence for two TIN2 subcomplexes with distinct functions in human cells. We isolated these two TIN2 subcomplexes from nuclear lysates of unperturbed cells and cells expressing TIN2 mutants TIN2-13 and TIN2-15C, which cannot bind TRF2 or TRF1, respectively. In cells with wild-type p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere uncapping and eventual growth arrest. In cells lacking p53 function, TIN2-15C was more potent than TIN2-13 in causing telomere dysfunction and cell death. Our findings suggest that distinct TIN2 complexes exist and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. skim3@hfhs.org
authors.forename: Sahn-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Albert R
authors.initials: AR
authors.lastname: Davalos
authors.forename: Seok-Jin
authors.initials: SJ
authors.lastname: Heo
authors.forename: Francis
authors.initials: F
authors.lastname: Rodier
authors.forename: Ying
authors.initials: Y
authors.lastname: Zou
authors.forename: Christian
authors.initials: C
authors.lastname: Beausejour
authors.forename: Patrick
authors.initials: P
authors.lastname: Kaminker
authors.forename: Steven M
authors.initials: SM
authors.lastname: Yannone
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D016922:Cellular Senescence / Q000502:physiology; D002869:Chromosome Aberrations; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D000089804:Shelterin Complex; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C495876:ACD protein, human; C544060:Acd protein, mouse; D046911:Macromolecular Substances; C440849:POT1 protein, human; D000089804:Shelterin Complex; C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D019098:Telomerase