title: ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres.
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 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.
authors.affiliation: Cell Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Tong
authors.affiliation: Cell Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: J Lewis
authors.initials: JL
authors.lastname: Stern
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Agnel
authors.initials: A
authors.lastname: Sfeir
authors.affiliation: Cell Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Kartawinata
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Zhu
authors.affiliation: Cell Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia. Electronic address: tbryan@cmri.org.au.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Bryan
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000235:genetics; D015003:Yeasts / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D011494:Protein Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D019098:Telomerase