Apollo contributes to G overhang maintenance and protects leading-end telomeres

Mol Cell. 2010 Aug 27;39(4):606-17. doi: 10.1016/j.molcel.2010.06.031. Epub 2010 Jul 8.

Abstract

Mammalian telomeres contain a single-stranded 3' overhang that is thought to mediate telomere protection. Here we identify the TRF2-interacting factor Apollo as a nuclease that contributes to the generation/maintenance of this overhang. The function of mouse Apollo was determined using Cre-mediated gene deletion, complementation with Apollo mutants, and the TRF2-F120A mutant that cannot bind Apollo. Cells lacking Apollo activated the ATM kinase at their telomeres in S phase and showed leading-end telomere fusions. These telomere dysfunction phenotypes were accompanied by a reduction in the telomeric overhang signal. The telomeric functions of Apollo required its TRF2-interaction and nuclease motifs. Thus, TRF2 recruits the Apollo nuclease to process telomere ends synthesized by leading-strand DNA synthesis, thereby creating a terminal structure that avoids ATM activation and resists end-joining. These data establish that the telomeric overhang is required for the protection of telomeres from the DNA damage response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • DNA Damage
  • DNA Replication*
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Exodeoxyribonucleases
  • Fibroblasts / enzymology*
  • G2 Phase
  • Gene Fusion
  • Genotype
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Nucleic Acid Conformation
  • Phenotype
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • S Phase
  • Telomere / chemistry
  • Telomere / metabolism*
  • Telomere-Binding Proteins / chemistry
  • Telomere-Binding Proteins / deficiency
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*
  • Telomeric Repeat Binding Protein 2 / metabolism
  • Time Factors
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • TRF2 protein, mouse
  • Telomere-Binding Proteins
  • Telomeric Repeat Binding Protein 2
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • Dclre1b protein, mouse
  • Exodeoxyribonucleases