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.
Copyright (c) 2010 Elsevier Inc. All rights reserved.
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