TRF2 and Apollo Cooperate with Topoisomerase 2α to Protect Human Telomeres from Replicative Damage

Jing Ye (1, 2, 3) , Christelle Lenain (2) , Serge Bauwens (2) , Angela Rizzo (4) , Adelaïde Saint-Léger (2, 3) , Anaïs Poulet (2, 5) , Delphine Benarroch (2, 3, 5) , Frédérique Magdinier (2) , Julia Morere (2) , Simon Amiard (2, 4, 5) , Els Verhoeyen (6) , Sébastien Britton (7) , Patrick Calsou (7) , Bernard Salles (7) , Anna Bizard (8) , Marc Nadal (8) , Erica Salvati (2, 4) , Laure Sabatier (9) , Yunlin Wu (1) , Annamaria Biroccio (4) , Arturo Londoño-Vallejo (10) , Marie-Josèphe Giraud-Panis (2, 5, 11) , Eric Gilson (2, 3, 12)

1 Shanghai Jiao Tong University School of Medicine
2 LBMC - Laboratoire de Biologie Moléculaire de la Cellule
3 Laboratoire de biologie et pathologie des génomes
4 Experimental Chemotherapy Laboratory
5 Laboratoire Joliot Curie
6 Virologie humaine
7 IPBS - Institut de pharmacologie et de biologie structurale
8 IGM - Institut de génétique et microbiologie [Orsay]
9 Laboratoire de Radiobiologie et d'Oncologie
10 UPMC - Université Pierre et Marie Curie - Paris 6
11 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
12 Department of Medical Genetics

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-β-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 2α 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, TOP2α, and TOP2β 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.

Domaines: Biologie cellulaire; Biochimie, Biologie Moléculaire; Microbiologie et Parasitologie

Jing Ye, Christelle Lenain, Serge Bauwens, Angela Rizzo, Adelaïde Saint-Léger, et al.. TRF2 and Apollo Cooperate with Topoisomerase 2α to Protect Human Telomeres from Replicative Damage. Cell, 2010, 142 (2), pp.230-242. ⟨10.1016/j.cell.2010.05.032⟩. ⟨ensl-00817706⟩