Article
- The EMBO Journal (2007) 26, 4709 - 4719
- doi:10.1038/sj.emboj.7601893
Published online: 18 October 2007
Subject Categories:
Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis
Xiaolan Guo1,2,5, Yibin Deng1,5, Yahong Lin1, Wilfredo Cosme-Blanco1, Suzanne Chan1, Hua He1, Guohua Yuan2, Eric J Brown3 and Sandy Chang1,4
- Department of Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Institute of Rheumatology and Immunology, North Sichuan Medical College, Nanchong, Sichuan, PR China
- Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- These authors contributed equally to this work
Correspondence to:
Yibin Deng, Department of Cancer Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Tel.: +1 713 834 6362; Fax: +1 713 834 6319; E-mail: yideng@mdanderson.org
Sandy Chang, Department of Hematopathology Cancer Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1006, Houston, TX 77030, USA. Tel.: +1 713 834 6361; Fax: +1 713 834 6319; E-mail: schang@mdanderson.org
Received 8 August 2007; Accepted 19 September 2007
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.
Keywords:
- ATM/ATR,
- chromosomal instability,
- DNA damage,
- telomere,
- tumorigenesis
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