TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage.
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.
Ye
Jing
J
Shanghai Ruijin Hospital, School of Medicine of Shanghai Jiaotong University, 200025 Shanghai, China.
Lenain
Christelle
C
Bauwens
Serge
S
Rizzo
Angela
A
Saint-Léger
Adelaïde
A
Poulet
Anaïs
A
Benarroch
Delphine
D
Magdinier
Frédérique
F
Morere
Julia
J
Amiard
Simon
S
Verhoeyen
Els
E
Britton
Sébastien
S
Calsou
Patrick
P
Salles
Bernard
B
Bizard
Anna
A
Nadal
Marc
M
Salvati
Erica
E
Sabatier
Laure
L
Wu
Yunlin
Y
Biroccio
Annamaria
A
Londoño-Vallejo
Arturo
A
Giraud-Panis
Marie-Josèphe
MJ
Gilson
Eric
E
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*
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