Article | Published:

Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1

Nature Structural & Molecular Biology volume 21, pages 167174 (2014) | Download Citation

Abstract

The mechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalian chromosome-end maintenance has been unclear. We have now discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies (APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomeric sister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. The induction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. We determined that ALT induction is positively regulated by the proteins RAD17 and BLM and negatively regulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletion strongly supports the hypothesis that ALT is a consequence of histone management dysfunction.

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Acknowledgements

We are indebted to H. Pickett (CMRI, Sydney, Australia) for generously sharing HT1080-hTR cells, reagents and for expert advice. We are grateful to Z. You (Washington University, St. Louis), J. Campbell (California Institute of Technology, Pasadena, California, USA), R. Everett (University of Glasgow), Z. Gurard-Levin (Institut Curie, Paris) and O. Fernandez-Capetillo (CNIO, Madrid, Spain) for sharing reagents. We thank the Salk Institute's J. Fitzpatrick of the Waitt Advanced Biophotonics Center (La Jolla, California, USA) for imaging assistance. R.J.O. is supported by the American Foundation for Aging Research (AFAR) and the Glenn Center for Research on Aging. N.A. is supported by a Human Frontier Science Program (HFSP) fellowship. D.H.L. and L.O. are supported by the Glenn Center for Research on Aging. G.A. is supported by La Ligue Nationale contre le Cancer (Equipe labellisée Ligue), PIC Programs, the European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082), the European Commission ITN FP7-PEOPLE-2008-238176 “Nucleosome 4D,” ERC Advanced Grant 2009-AdG_20090506 “Eccentric,” the European Commission large-scale integrating project FP7_HEALTH-2010-259743 “MODHEP,” ANR “ChromaTin” ANR-10-BLAN-1326-03, ANR-11-LABX-0044_DEEP and ANR-10-IDEX-0001-02 PSL*, ANR “CHAPINHIB” ANR-12-BSV5-0022-02 and Aviesan-ITMO cancer project “Epigenomics of breast cancer.” J.K. is supported by the Salk Institute Cancer Center Core Grant (P30CA014195), the US National Institutes of Health (R01GM087476, R01CA174942), the Sabo Trust, the Fritz B. Burns Foundation, Philip Messinger and the Highland Street Foundation.

Author information

Author notes

    • Armelle Corpet

    Present address: University Hospital of Zurich, Zurich, Switzerland.

Affiliations

  1. Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA.

    • Roderick J O'Sullivan
    • , Nausica Arnoult
    • , Daniel H Lackner
    • , Liana Oganesian
    • , Candy Haggblom
    •  & Jan Karlseder
  2. Institut Curie, Centre de Recherche, Paris, France.

    • Armelle Corpet
    •  & Genevieve Almouzni
  3. Centre National de la Recherche Scientifique, Paris, France.

    • Armelle Corpet
    •  & Genevieve Almouzni

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Contributions

R.J.O. designed and carried out the experiments and wrote the manuscript. N.A., L.O. and C.H. designed and carried out experiments. D.H.L. analyzed microarray data. A.C. provided essential reagents and contributed to the original concept of the project. G.A. provided essential reagents, contributed to the original concept of the project and provided additional support throughout. J.K. designed experiments, supervised the work and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jan Karlseder.

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https://doi.org/10.1038/nsmb.2754

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