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

• ATM and ATR are required for telomerase recruitment to telomeres in human cells
• Replication fork stalling triggers ATR-dependent telomerase recruitment to telomeres
• Phosphorylation of TRF1 at an SQ site contributes to telomerase recruitment
• ATM is required for telomere elongation in vivo

SummaryThe 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 POT1ΔOB, 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.

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