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PMID: 17948054 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.

The EMBO journal ·Vol. 26 ·No. 22 ·2007-11-14 ·Pages 4709-19

Guo X, Deng Y, Lin Y, Cosme-Blanco W, Chan S, He H, Yuan G, Brown EJ, Chang S

Abstract

The POT1 (protection of telomeres) protein binds the single-stranded G-rich overhang and is essential for both telomere end protection and telomere length regulation. Telomeric binding of POT1 is enhanced by its interaction with TPP1. In this study, we demonstrate that mouse Tpp1 confers telomere end protection by recruiting Pot1a and Pot1b to telomeres. Knockdown of Tpp1 elicits a p53-dependent growth arrest and an ATM-dependent DNA damage response at telomeres. In contrast to depletion of Trf2, which activates ATM, removal of Pot1a and Pot1b from telomeres initiates an ATR-dependent DNA damage response (DDR). Finally, we show that telomere dysfunction as a result of Tpp1 depletion promotes chromosomal instability and tumorigenesis in the absence of an ATM-dependent DDR. Our results uncover a novel ATR-dependent DDR at telomeres that is normally shielded by POT1 binding to the single-stranded G-overhang. In addition, our results suggest that loss of ATM can cooperate with dysfunctional telomeres to promote cellular transformation and tumor formation in vivo.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/metabolism Cells, Cultured DNA Damage DNA-Binding Proteins/metabolism Embryo, Mammalian/cytology Fibroblasts/metabolism Mice Neoplasms/genetics,metabolism Protein Serine-Threonine Kinases/metabolism RNA, Messenger/metabolism Shelterin Complex Telomere/genetics,metabolism Telomere-Binding Proteins/deficiency,genetics,metabolism Telomeric Repeat Binding Protein 2/metabolism Tripeptidyl-Peptidase 1 Tumor Suppressor Proteins/metabolism
Chemicals
ACD protein, human Cell Cycle Proteins DNA-Binding Proteins POT1 protein, mouse POT1b protein, mouse RNA, Messenger Shelterin Complex Telomere-Binding Proteins Telomeric Repeat Binding Protein 2 Tpp1 protein, mouse Tripeptidyl-Peptidase 1 Tumor Suppressor Proteins Atr protein, mouse ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases TPP1 protein, human
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Guo Xiaolan
Department of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Deng Yibin
Lin Yahong
Cosme-Blanco Wilfredo
Chan Suzanne
He Hua
Yuan Guohua
Brown Eric J
Chang Sandy
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/sj.emboj.7601893
Published
2007-11-14
Epub
2007-00-18
Pages
4709-19
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2080807
Subset
IM
Grants
NCI NIH HHS · K01 CA124461 · United States
NIA NIH HHS · R01 AG028888 · United States
NCI NIH HHS · R01 CA129037 · United States
NCI NIH HHS · 1K01CA124461 · United States
External Links
PubMed source DOI: 10.1038/sj.emboj.7601893 PMC Full Text View journal details
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