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

Xiaolan Guo, Yibin Deng, Yahong Lin, Wilfredo Cosme-Blanco, Suzanne Chan, Hua He, Guohua Yuan, Eric J. Brown, Sandy Chang

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4709-4719
Number of pages11
JournalEMBO Journal
Volume26
Issue number22
DOIs
StatePublished - Nov 14 2007

Keywords

  • ATM/ATR
  • Chromosomal instability
  • DNA damage
  • Telomere
  • Tumorigenesis

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