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

Journal Article · · Journal of Cell Biology
 [1];  [2];  [2];  [2];  [2];  [2];  [3];  [2];  [4]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; DOE/OSTI
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
  3. Buck Inst. for Age Research, Novato, CA (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division; Buck Inst. for Age Research, Novato, CA (United States)
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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.

Research Organization:
Lawrence Berkeley National Lab. (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
OSTI ID:
1625145
Journal Information:
Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 3 Vol. 181; ISSN 0021-9525
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (17)

Structural Basis of Selective Ubiquitination of TRF1 by SCFFbx4 journal February 2010
Structural identity of telomeric complexes journal August 2010
GNL3L stabilizes the TRF1 complex and promotes mitotic transition journal June 2009
Loss of RNA-binding protein HuR facilitates cellular senescence through posttranscriptional regulation of TIN2 mRNA journal March 2018
Mir‐23a induces telomere dysfunction and cellular senescence by inhibiting TRF 2 expression journal March 2015
Targeting the telomere and shelterin complex for cancer therapy: current views and future perspectives journal February 2011
The C-Terminal Extension Unique to the Long Isoform of the Shelterin Component TIN2 Enhances Its Interaction with TRF2 in a Phosphorylation- and Dyskeratosis Congenita Cluster-Dependent Fashion journal June 2018
Tpz1-Ccq1 and Tpz1-Poz1 Interactions within Fission Yeast Shelterin Modulate Ccq1 Thr93 Phosphorylation and Telomerase Recruitment journal October 2014
The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres journal July 2015
A Versatile Viral System for Expression and Depletion of Proteins in Mammalian Cells journal August 2009
Structural and functional association of androgen receptor with telomeres in prostate cancer cells journal January 2013
Klotho-Mediated Changes in Shelterin Complex Promote Cytotoxic Autophagy and Apoptosis in Amitriptyline-Treated Hippocampal Neuronal Cells journal April 2019
Trypanosoma brucei TIF2 suppresses VSG switching by maintaining subtelomere integrity journal May 2014
Human RAP1 inhibits non-homologous end joining at telomeres journal September 2009
Telomeres and telomerase in prostate cancer development and therapy journal July 2017
TIN2 Protein Dyskeratosis Congenita Missense Mutants Are Defective in Association with Telomerase journal July 2011
Telomeric dysfunction triggers an unstable growth arrest leading to irreparable genomic lesions and entry into cellular senescence posted_content October 2018

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59 BASIC BIOLOGICAL SCIENCES
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