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Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX

Author

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  • David Clynes

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Clare Jelinska

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Barbara Xella

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Helena Ayyub

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Caroline Scott

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Matthew Mitson

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Stephen Taylor

    (Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Douglas R. Higgs

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

  • Richard J. Gibbons

    (MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital)

Abstract

Fifteen per cent of cancers maintain telomere length independently of telomerase by the homologous recombination (HR)-associated alternative lengthening of telomeres (ALT) pathway. A unifying feature of these tumours are mutations in ATRX. Here we show that expression of ectopic ATRX triggers a suppression of the pathway and telomere shortening. Importantly ATRX-mediated ALT suppression is dependent on the histone chaperone DAXX. Re-expression of ATRX is associated with a reduction in replication fork stalling, a known trigger for HR and loss of MRN from telomeres. A G-quadruplex stabilizer partially reverses the effect of ATRX, inferring ATRX may normally facilitate replication through these sequences that, if they persist, promote ALT. We propose that defective telomere chromatinization through loss of ATRX promotes the persistence of aberrant DNA secondary structures, which in turn present a barrier to DNA replication, leading to replication fork stalling, collapse, HR and subsequent recombination-mediated telomere synthesis in ALT cancers.

Suggested Citation

  • David Clynes & Clare Jelinska & Barbara Xella & Helena Ayyub & Caroline Scott & Matthew Mitson & Stephen Taylor & Douglas R. Higgs & Richard J. Gibbons, 2015. "Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8538
    DOI: 10.1038/ncomms8538
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    Cited by:

    1. Courtney A Lovejoy & Kaori Takai & Michael S Huh & David J Picketts & Titia de Lange, 2020. "ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity," PLOS Biology, Public Library of Science, vol. 18(1), pages 1-28, January.
    2. Nitish Gulve & Chenhe Su & Zhong Deng & Samantha S. Soldan & Olga Vladimirova & Jayamanna Wickramasinghe & Hongwu Zheng & Andrew V. Kossenkov & Paul. M. Lieberman, 2022. "DAXX-ATRX regulation of p53 chromatin binding and DNA damage response," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Julia Truch & Damien J. Downes & Caroline Scott & E. Ravza Gür & Jelena M. Telenius & Emmanouela Repapi & Ron Schwessinger & Matthew Gosden & Jill M. Brown & Stephen Taylor & Pak Leng Cheong & Jim R. , 2022. "The chromatin remodeller ATRX facilitates diverse nuclear processes, in a stochastic manner, in both heterochromatin and euchromatin," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Timothy K. Turkalo & Antonio Maffia & Johannes J. Schabort & Samuel G. Regalado & Mital Bhakta & Marco Blanchette & Diana C. J. Spierings & Peter M. Lansdorp & Dirk Hockemeyer, 2023. "A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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