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Published online April 28, 2008
doi:10.1083/jcb.200710028
The Journal of Cell Biology, Vol. 181, No. 3, 447-460
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Kim et al.
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Article

 Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes

Sahn-ho Kim1, Albert R. Davalos1, Seok-Jin Heo1, Francis Rodier1, Ying Zou1, Christian Beausejour1, Patrick Kaminker2, Steven M. Yannone1, and Judith Campisi1,2

1 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
2 Buck Institute for Age Research, Novato, CA 94945

Correspondence to S.-h. Kim: skim3{at}hfhs.org

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.

S.-h. Kim's present address is Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI 48202.

C. Beausejour's present address is Département de Pharmacologie Centre de Recherche, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Quebec H3T 1C5, Canada.

P. Kaminker's present address is Human Genome Sciences, Rockville, MD 20850.

Abbreviations used in this paper: DN-TRF2, dominant-negative TRF2; POT1, protector of telomeres 1; PNA, protein nucleic acid; shRNA, short hairpin RNA; TIN2, TRF1-interacting protein 2; TRF, telomeric repeat binding factor.


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