title: TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage.
abstract: Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding partner, Apollo, a member of the metallo-beta-lactamase family that is required for telomere integrity during S phase. TRF2 and Apollo also suppress damage to engineered interstitial telomere repeat tracts that were inserted far away from chromosome ends. Genetic data indicate that DNA topoisomerase 2alpha acts in the same pathway of telomere protection as TRF2 and Apollo. Moreover, TRF2, which binds preferentially to positively supercoiled DNA substrates, together with Apollo, negatively regulates the amount of TOP1, TOP2alpha, and TOP2beta at telomeres. Our data are consistent with a model in which TRF2 and Apollo relieve topological stress during telomere replication. Our work also suggests that cellular senescence may be caused by topological problems that occur during the replication of the inner portion of telomeres.
authors.affiliation: Shanghai Ruijin Hospital, School of Medicine of Shanghai Jiaotong University, 200025 Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.forename: Christelle
authors.initials: C
authors.lastname: Lenain
authors.forename: Serge
authors.initials: S
authors.lastname: Bauwens
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.forename: Adelaïde
authors.initials: A
authors.lastname: Saint-Léger
authors.forename: Anaïs
authors.initials: A
authors.lastname: Poulet
authors.forename: Delphine
authors.initials: D
authors.lastname: Benarroch
authors.forename: Frédérique
authors.initials: F
authors.lastname: Magdinier
authors.forename: Julia
authors.initials: J
authors.lastname: Morere
authors.forename: Simon
authors.initials: S
authors.lastname: Amiard
authors.forename: Els
authors.initials: E
authors.lastname: Verhoeyen
authors.forename: Sébastien
authors.initials: S
authors.lastname: Britton
authors.forename: Patrick
authors.initials: P
authors.lastname: Calsou
authors.forename: Bernard
authors.initials: B
authors.lastname: Salles
authors.forename: Anna
authors.initials: A
authors.lastname: Bizard
authors.forename: Marc
authors.initials: M
authors.lastname: Nadal
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
authors.forename: Yunlin
authors.initials: Y
authors.lastname: Wu
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.forename: Arturo
authors.initials: A
authors.lastname: Londoño-Vallejo
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Giraud-Panis
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D016922:Cellular Senescence; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004261:DNA Replication; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005090:Exodeoxyribonucleases; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D004250:DNA Topoisomerases, Type II; D045643:DNA Repair Enzymes