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Sci Adv. 2019 May 8;5(5):eaav3673. doi: 10.1126/sciadv.aav3673. eCollection 2019 May.

SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres.

Author information

1
Institute of Human Genetics CNRS-Université de Montpellier UMR 9002, 141 rue de la Cardonille, Montpellier 34000, France.
2
Department of Microbiology and Infectious Diseases, PRAC-Université de Sherbrooke 3201 Jean-Mignault, Sherbrooke, Qc J1E 4K8, Canada.
3
Munich Centre of Integrated Protein Science and Division of Molecular Biology Biomedical Center, Faculty of Medicine, LMU Munich, Großhaderner Str.9 82152 Planegg, Martinsried, Germany.
4
Functional Proteomics Facility, Institute of Functional Genomics, 141 rue de la Cardonille, 34000 Montpellier, France.

Abstract

Alternative lengthening of telomeres, or ALT, is a recombination-based process that maintains telomeres to render some cancer cells immortal. The prevailing view is that ALT is inhibited by heterochromatin because heterochromatin prevents recombination. To test this model, we used telomere-specific quantitative proteomics on cells with heterochromatin deficiencies. In contrast to expectations, we found that ALT does not result from a lack of heterochromatin; rather, ALT is a consequence of heterochromatin formation at telomeres, which is seeded by the histone methyltransferase SETDB1. Heterochromatin stimulates transcriptional elongation at telomeres together with the recruitment of recombination factors, while disrupting heterochromatin had the opposite effect. Consistently, loss of SETDB1, disrupts telomeric heterochromatin and abrogates ALT. Thus, inhibiting telomeric heterochromatin formation in ALT cells might offer a new therapeutic approach to cancer treatment.

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