ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres

Academic Article

Abstract

  • The yeast homologs of the ATM and ATR DNA damage response kinases play key roles in telomerase-mediated telomere maintenance, but the role of ATM/ATR in the mammalian telomerase pathway has been less clear. Here, we demonstrate the requirement for ATM and ATR in the localization of telomerase to telomeres and telomere elongation in immortal human cells. Stalled replication forks increased telomerase recruitment in an ATR-dependent manner. Furthermore, increased telomerase recruitment was observed upon phosphorylation of the shelterin component TRF1 at an ATM/ATR target site (S367). This phosphorylation leads to loss of TRF1 from telomeres and may therefore increase replication fork stalling. ATM and ATR depletion reduced assembly of the telomerase complex, and ATM was required for telomere elongation in cells expressing POT1╬┤OB, an allele of POT1 that disrupts telomere-length homeostasis. These data establish that human telomerase recruitment and telomere elongation are modulated by DNA-damage-transducing kinases. Tong et al. demonstrate that the DNA damage response kinases ATM and ATR are required for the presence of telomerase at telomeres in human cells. Replication fork stalling triggers ATR-mediated telomerase recruitment, and phosphorylation of the telomere-binding protein TRF1 at serine 367 also regulates the presence of telomerase at telomeres.
  • Authors

    Published In

  • Cell Reports  Journal
  • Digital Object Identifier (doi)

    Pubmed Id

  • 25408882
  • Author List

  • Tong AS; Stern JL; Sfeir A; Kartawinata M; de Lange T; Zhu XD; Bryan TM
  • Start Page

  • 1633
  • End Page

  • 1646
  • Volume

  • 13
  • Issue

  • 8