Article
- The EMBO Journal (2008) 27, 1513 - 1524
- doi:10.1038/emboj.2008.74
Published online: 17 April 2008
Subject Categories:
Topoisomerase III
is required for normal proliferation and telomere stability in alternative lengthening of telomeres
Nassima Temime-Smaali1,a, Lionel Guittat1,2,a, Thomas Wenner1,a, Emilie Bayart3, Céline Douarre1, Dennis Gomez4, Marie-Josèphe Giraud-Panis5, Arturo Londono-Vallejo6, Eric Gilson5, Mounira Amor-Guéret3 and Jean-François Riou1,2
- Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
- Laboratoire de Régulation et dynamique des génomes, INSERM U565, CNRS UMR5153, Muséum National d'Histoire Naturelle USM503, Paris, France
- Institut Curie, Section de Recherche, CNRS UMR 2027, Centre Universitaire, Orsay, France
- Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089, Toulouse, France
- Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5239, Ecole Normale Supérieure de Lyon, Lyon, France
- Laboratoire Télomères et Cancer, CNRS UMR 7147, Institut Curie, Paris, France
Correspondence to:
Jean-François Riou, Laboratoire de Régulation et dynamique des génomes, INSERM U565, CNRS UMR5153, Muséum National d'Histoire Naturelle USM503, 43 rue Cuvier, CP26, 75231 Paris Cedex 5, France. Tel.: +33 1 40 79 36 98; Fax: +33 1 40 79 37 05; E-mail: riou@mnhn.fr
aThese authors contributed equally to this work
Received 12 July 2007; Accepted 19 March 2008
Abstract
Topoisomerase (Topo) III
associates with BLM helicase, which is proposed to be important in the alternative lengthening of telomeres (ALT) pathway that allows telomere recombination in the absence of telomerase. Here, we show that human Topo III colocalizes with telomeric proteins at ALT-associated promyelocytic bodies from ALT cells. In these cells, Topo III immunoprecipitated with telomere binding protein (TRF) 2 and BLM and was shown to be associated with telomeric DNA by chromatin immunoprecipitation, suggesting that these proteins form a complex at telomere sequences. Topo III depletion by small interfering RNA reduced ALT cell survival, but did not affect telomerase-positive cell lines. Moreover, repression of Topo III expression in ALT cells reduced the levels of TRF2 and BLM proteins, provoked a strong increase in the formation of anaphase bridges, induced the degradation of the G-overhang signal, and resulted in the appearance of DNA damage at telomeres. In contrast, telomere maintenance and TRF2 levels were unaffected in telomerase-positive cells. We conclude that Topo III is an important telomere-associated factor, essential for telomere maintenance and chromosome stability in ALT cells, and speculate on its potential mechanistic function.
Keywords:
- ALT,
- BLM,
- G-overhang,
- telomere,
- topoisomerase; TRF2
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