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Molecular mechanisms of activity and derepression of alternative lengthening of telomeres

Nature Structural & Molecular Biology volume 22, pages 875–880 (2015)Cite this article

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Abstract

Alternative lengthening of telomeres (ALT) involves homology-directed telomere synthesis. This multistep process is facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture, including altered DNA sequence and decreased TRF2 saturation. Induction of telomere-specific DNA damage triggers homology-directed searches, and NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins. Telomere lengthening proceeds by strand exchange and template-driven DNA synthesis, which culminates in dissolution of HR intermediates.

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Figure 1: Four putative steps in the ALT mechanism.
Figure 2: Adjacent and distant copy templates in ALT.
Figure 3: Multiple roles of the NuRD–ZNF827 complex at ALT telomeres.

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Acknowledgements

Work in the authors' laboratories is supported by Cancer Institute New South Wales (NSW) Career Development Fellowship (H.A.P.), Cancer Council NSW Project Grant ID1069550 (H.A.P.) and Program Grant PG11-08 (R.R.R.), and National Health and Medical Research Council of Australia Project Grants ID 1009231 (H.A.P. and R.R.R.), 1034564 (R.R.R.) and 1088646 (R.R.R.). We thank E. Collins for assistance in preparing the manuscript.

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  1. Telomere Length Regulation Group, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia

    Hilda A Pickett

  2. Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia

    Roger R Reddel

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Correspondence to Hilda A Pickett or Roger R Reddel.

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Pickett, H., Reddel, R. Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nat Struct Mol Biol 22, 875–880 (2015). https://doi.org/10.1038/nsmb.3106

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