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

Kim, Sahn-ho; Davalos, Albert R.; Heo, Seok-Jin; Rodier, Francis; Zou, Ying; Beausejour, Christian; Kaminker, Patrick; Yannone, Steven M.; Campisi, Judith

doi:10.1083/jcb.200710028

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

Journal Article · Mon Apr 28 00:00:00 EDT 2008 · Journal of Cell Biology

DOI:https://doi.org/10.1083/jcb.200710028· OSTI ID:1625145

Kim, Sahn-ho ^[1]; Davalos, Albert R. ^[1]; Heo, Seok-Jin ^[1]; Rodier, Francis ^[1]; Zou, Ying ^[1]; Beausejour, Christian ^[1]; Kaminker, Patrick ^[2]; Yannone, Steven M. ^[1]; Campisi, Judith ^[3]

Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
Buck Inst. for Age Research, Novato, CA (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Buck Inst. for Age Research, Novato, CA (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231; AC03-76SF00098; AG011658-12; AG024399-02; CA107798A

OSTI ID:: 1625145

Journal Information:: Journal of Cell Biology, Vol. 181, Issue 3; ISSN 0021-9525

Publisher:: Rockefeller University PressCopyright Statement

Country of Publication:: United States

Language:: English

References (53)

A Third-Generation Lentivirus Vector with a Conditional Packaging System Dull, Tom; Zufferey, Romain; Kelly, Michael Journal of Virology, Vol. 72, Issue 11 https://doi.org/10.1128/JVI.72.11.8463-8471.1998	journal	November 1998
TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase Xin, Huawei; Liu, Dan; Wan, Ma Nature, Vol. 445, Issue 7127 https://doi.org/10.1038/nature05469	journal	January 2007
A DNA damage checkpoint response in telomere-initiated senescence Fagagna, Fabrizio d'Adda di; Reaper, Philip M.; Clay-Farrace, Lorena Nature, Vol. 426, Issue 6963 https://doi.org/10.1038/nature02118	journal	November 2003
POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex Ye, J. Z. -S. Genes & Development, Vol. 18, Issue 14 https://doi.org/10.1101/gad.1215404	journal	July 2004
Inhibition of p53 by Lentiviral Mediated sh RNA Abrogates G ₁ Arrest and Apoptosis in Retinal Pigmented Epithelial Cell Line Nair, Ayyappan R.; Schliekelman, Mark; Thomas, Mary Beth Cell Cycle, Vol. 4, Issue 5 https://doi.org/10.4161/cc.4.5.1672	journal	March 2005
A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly O'Connor, M. S.; Safari, A.; Xin, H. Proceedings of the National Academy of Sciences, Vol. 103, Issue 32 https://doi.org/10.1073/pnas.0605303103	journal	July 2006
A System for Stable Expression of Short Interfering RNAs in Mammalian Cells Brummelkamp, T. R. Science, Vol. 296, Issue 5567 https://doi.org/10.1126/science.1068999	journal	March 2002
Roles of the BRD4 short isoform in phase separation and active gene transcription Han, Xinye; Yu, Di; Gu, Ruirui Nature Structural & Molecular Biology, Vol. 27, Issue 4 https://doi.org/10.1038/s41594-020-0394-8	journal	March 2020
Pot1, the Putative Telomere End-Binding Protein in Fission Yeast and Humans Baumann, P. Science, Vol. 292, Issue 5519 https://doi.org/10.1126/science.1060036	journal	May 2001
Inhibition of telomerase limits the growth of human cancer cells Hahn, William C.; Stewart, Sheila A.; Brooks, Mary W. Nature Medicine, Vol. 5, Issue 10 https://doi.org/10.1038/13495	journal	October 1999
The human telomere‐associated protein TIN2 stimulates interactions between telomeric DNA tracts in vitro Kim, Sahn‐Ho; Han, Seungil; You, Young‐Hyun EMBO reports, Vol. 4, Issue 7 https://doi.org/10.1038/sj.embor.embor872	journal	June 2003
POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end Hockemeyer, Dirk; Sfeir, Agnel J.; Shay, Jerry W. The EMBO Journal, Vol. 24, Issue 14 https://doi.org/10.1038/sj.emboj.7600733	journal	June 2005
A Dynamic Molecular Link between the Telomere Length Regulator TRF1 and the Chromosome End Protector TRF2 Houghtaling, Benjamin R.; Cuttonaro, Leanora; Chang, William Current Biology, Vol. 14, Issue 18 https://doi.org/10.1016/j.cub.2004.08.052	journal	September 2004
Reversal of human cellular senescence: roles of the p53 and p16 pathways Beausejour, C. M. The EMBO Journal, Vol. 22, Issue 16 https://doi.org/10.1093/emboj/cdg417	journal	August 2003
DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion Celli, Giulia B.; de Lange, Titia Nature Cell Biology, Vol. 7, Issue 7 https://doi.org/10.1038/ncb1275	journal	June 2005
TRF1 binds a bipartite telomeric site with extreme spatial flexibility Daniela, Rhodes,; D., Griffith, Jack; Louise, Fairall, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/cjt0-eh49	text	January 1999
Recent Expansion of the Telomeric Complex in Rodents: Two Distinct POT1 Proteins Protect Mouse Telomeres Hockemeyer, Dirk; Daniels, Jan-Peter; Takai, Hiroyuki Cell, Vol. 126, Issue 1 https://doi.org/10.1016/j.cell.2006.04.044	journal	July 2006
Expression of mutant telomerase in immortal telomerase-negative human cells results in cell cycle deregulation, nuclear and chromosomal abnormalities and rapid loss of viability Guiducci, Cristiana; Cerone, Maria Antonietta; Bacchetti, Silvia Oncogene, Vol. 20, Issue 6 https://doi.org/10.1038/sj.onc.1204145	journal	February 2001
TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres Chang, W. Genes & Development, Vol. 17, Issue >11 https://doi.org/10.1101/gad.1077103	journal	June 2003
Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks Davalos, Albert R.; Campisi, Judith Journal of Cell Biology, Vol. 162, Issue 7 https://doi.org/10.1083/jcb.200304016	journal	September 2003
Regulation of Telomerase by Telomeric Proteins Smogorzewska, Agata; de Lange, Titia Annual Review of Biochemistry, Vol. 73, Issue 1 https://doi.org/10.1146/annurev.biochem.73.071403.160049	journal	June 2004
POT1 as a terminal transducer of TRF1 telomere length control Loayza, Diego; de Lange, Titia Nature, Vol. 423, Issue 6943 https://doi.org/10.1038/nature01688	journal	May 2003
Pot1 Deficiency Initiates DNA Damage Checkpoint Activation and Aberrant Homologous Recombination at Telomeres Wu, Ling; Multani, Asha S.; He, Hua Cell, Vol. 126, Issue 1 https://doi.org/10.1016/j.cell.2006.05.037	journal	July 2006
TIN2, a new regulator of telomere length in human cells Kim, Sahn-ho; Kaminker, Patrick; Campisi, Judith Nature Genetics, Vol. 23, Issue 4 https://doi.org/10.1038/70508	journal	December 1999
Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei Dignam, J. D.; Lebovitz, R. M.; Roeder, R. G. Nucleic Acids Research, Vol. 11, Issue 5 https://doi.org/10.1093/nar/11.5.1475	journal	March 1983
Control of telomere length by the human telomeric protein TRF1 van Steensel, Bas; de Lange, Titia Nature, Vol. 385, Issue 6618 https://doi.org/10.1038/385740a0	journal	February 1997
TRF1 binds a bipartite telomeric site with extreme spatial flexibility Bianchi, A. The EMBO Journal, Vol. 18, Issue 20 https://doi.org/10.1093/emboj/18.20.5735	journal	October 1999
Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a Herbig, Utz; Jobling, Wendy A.; Chen, Benjamin P. C. Molecular Cell, Vol. 14, Issue 4 https://doi.org/10.1016/S1097-2765(04)00256-4	journal	May 2004
PTOP interacts with POT1 and regulates its localization to telomeres Liu, Dan; Safari, Amin; O'Connor, Matthew S. Nature Cell Biology, Vol. 6, Issue 7 https://doi.org/10.1038/ncb1142	journal	June 2004
A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Dimri, G. P.; Lee, X.; Basile, G. Proceedings of the National Academy of Sciences, Vol. 92, Issue 20 https://doi.org/10.1073/pnas.92.20.9363	journal	September 1995
Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA. Gudkov, A. V.; Zelnick, C. R.; Kazarov, A. R. Proceedings of the National Academy of Sciences, Vol. 90, Issue 8 https://doi.org/10.1073/pnas.90.8.3231	journal	April 1993
DNA double-strand break repair proteins are required to cap the ends of mammalian chromosomes Bailey, S. M.; Meyne, J.; Chen, D. J. Proceedings of the National Academy of Sciences, Vol. 96, Issue 26 https://doi.org/10.1073/pnas.96.26.14899	journal	December 1999
Does a Sentinel or a Subset of Short Telomeres Determine Replicative Senescence? Zou, Ying; Sfeir, Agnel; Gryaznov, Sergei M. Molecular Biology of the Cell, Vol. 15, Issue 8 https://doi.org/10.1091/mbc.e04-03-0207	journal	August 2004
Shelterin: the protein complex that shapes and safeguards human telomeres de Lange, T. Genes & Development, Vol. 19, Issue 18 https://doi.org/10.1101/gad.1346005	journal	September 2005
Telomere states and cell fates Blackburn, Elizabeth H. Nature, Vol. 408, Issue 6808 https://doi.org/10.1038/35040500	journal	November 2000
Cancer and aging: the importance of telomeres in genome maintenance Rodier, Francis; Kim, Sahn-Ho; Nijjar, Tarlochan The International Journal of Biochemistry & Cell Biology, Vol. 37, Issue 5 https://doi.org/10.1016/j.biocel.2004.10.012	journal	May 2005
Telomere analysis by fluorescence in situ hybridization and flow cytometry Hultdin, M.; Gronlund, E.; Norrback, K. - F. Nucleic Acids Research, Vol. 26, Issue 16 https://doi.org/10.1093/nar/26.16.3651	journal	August 1998
Different telomere damage signaling pathways in human and mouse cells Smogorzewska, A. The EMBO Journal, Vol. 21, Issue 16 https://doi.org/10.1093/emboj/cdf433	journal	August 2002
p53- and ATM-Dependent Apoptosis Induced by Telomeres Lacking TRF2 Karlseder, J. Science, Vol. 283, Issue 5406 https://doi.org/10.1126/science.283.5406.1321	journal	February 1999
Mammalian Telomeres End in a Large Duplex Loop Griffith, Jack D.; Comeau, Laurey; Rosenfield, Soraya Cell, Vol. 97, Issue 4 https://doi.org/10.1016/S0092-8674(00)80760-6	journal	May 1999
Caspase-independent cytochrome c release is a sensitive measure of low-level apoptosis in cell culture models Goldstein, Joshua C.; Rodier, Francis; Garbe, James C. Aging Cell, Vol. 4, Issue 4 https://doi.org/10.1111/j.1474-9726.2005.00163.x	journal	August 2005
Are Mouse Telomeres Going to Pot? Baumann, Peter Cell, Vol. 126, Issue 1 https://doi.org/10.1016/j.cell.2006.06.027	journal	July 2006
Telomeres Do D-Loop–T-Loop Greider, Carol W. Cell, Vol. 97, Issue 4 https://doi.org/10.1016/s0092-8674(00)80750-3	journal	May 1999
p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis Chin, Lynda; Artandi, Steven E.; Shen, Qiong Cell, Vol. 97, Issue 4 https://doi.org/10.1016/s0092-8674(00)80762-x	journal	May 1999
DNA Damage Foci at Dysfunctional Telomeres Takai, Hiroyuki; Smogorzewska, Agata; de Lange, Titia Current Biology, Vol. 13, Issue 17 https://doi.org/10.1016/s0960-9822(03)00542-6	journal	September 2003
Importance of TRF1 for Functional Telomere Structure Iwano, Tomohiko; Tachibana, Makoto; Reth, Michael Journal of Biological Chemistry, Vol. 279, Issue 2 https://doi.org/10.1074/jbc.m309138200	journal	January 2004
TIN2 Mediates Functions of TRF2 at Human Telomeres Kim, Sahn-ho; Beausejour, Christian; Davalos, Albert R. Journal of Biological Chemistry, Vol. 279, Issue 42 https://doi.org/10.1074/jbc.m408650200	journal	October 2004
TIN2 Binds TRF1 and TRF2 Simultaneously and Stabilizes the TRF2 Complex on Telomeres Ye, Jeffrey Zheng-Sheng; Donigian, Jill R.; van Overbeek, Megan Journal of Biological Chemistry, Vol. 279, Issue 45 https://doi.org/10.1074/jbc.m409047200	journal	November 2004
Limited capacity of the nuclear matrix to bind telomere repeat binding factor TRF1 may restrict the proliferation of mortal human fibroblasts Okabe, J. Human Molecular Genetics, Vol. 13, Issue 3 https://doi.org/10.1093/hmg/ddh032	journal	December 2003
Human Pot1 (Protection of Telomeres) Protein: Cytolocalization, Gene Structure, and Alternative Splicing Baumann, Peter; Podell, Elaine; Cech, Thomas R. Molecular and Cellular Biology, Vol. 22, Issue 22 https://doi.org/10.1128/mcb.22.22.8079-8087.2002	journal	November 2002
Telomere-Associated Protein TIN2 Is Essential for Early Embryonic Development through a Telomerase-Independent Pathway Chiang, Y. Jeffrey; Kim, Sahn-Ho; Tessarollo, Lino Molecular and Cellular Biology, Vol. 24, Issue 15 https://doi.org/10.1128/mcb.24.15.6631-6634.2004	journal	August 2004
POT1 and TRF2 Cooperate To Maintain Telomeric Integrity Yang, Qin; Zheng, Yun-Ling; Harris, Curtis C. Molecular and Cellular Biology, Vol. 25, Issue 3 https://doi.org/10.1128/mcb.25.3.1070-1080.2005	journal	February 2005
Rapid Inhibition of Cancer Cell Growth Induced by Lentiviral Delivery and Expression of Mutant-Template Telomerase RNA and Anti-telomerase Short-Interfering RNA Li, Shang; Rosenberg, Jonathan E.; Donjacour, Annemarie A. Cancer Research, Vol. 64, Issue 14 https://doi.org/10.1158/0008-5472.can-04-0953	journal	July 2004

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