TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage

Cell. 2010 Jul 23;142(2):230-42. doi: 10.1016/j.cell.2010.05.032.

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

Affiliations

Affiliation

1 Shanghai Ruijin Hospital, School of Medicine of Shanghai Jiaotong University, 200025 Shanghai, China.

PMID: 20655466 DOI: 10.1016/j.cell.2010.05.032

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.

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