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ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity

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  • Courtney A Lovejoy
  • Kaori Takai
  • Michael S Huh
  • David J Picketts
  • Titia de Lange

Abstract

Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.The chromatin remodeller ATRX is often lost in cells that maintain their telomeres using the telomerase-independent “alternative lengthening of telomeres” (ALT) pathway. This study shows how loss of ATRX alters the repair of telomeric DNA breaks and suggests how this change could promote telomere maintenance in ALT cells.

Suggested Citation

  • 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.
  • Handle: RePEc:plo:pbio00:3000594
    DOI: 10.1371/journal.pbio.3000594
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    References listed on IDEAS

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    1. Robert L. Dilley & Priyanka Verma & Nam Woo Cho & Harrison D. Winters & Anne R. Wondisford & Roger A. Greenberg, 2016. "Break-induced telomere synthesis underlies alternative telomere maintenance," Nature, Nature, vol. 539(7627), pages 54-58, November.
    2. 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.
    3. Marta Kovatcheva & Will Liao & Mary E. Klein & Nicolas Robine & Heather Geiger & Aimee M. Crago & Mark A. Dickson & William D. Tap & Samuel Singer & Andrew Koff, 2017. "ATRX is a regulator of therapy induced senescence in human cells," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
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    1. 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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