SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres

Mathilde Gauchier; Sophie Kan; Amandine Barral; Sandrine Sauzet; Eneritz Agirre; Erin Bonnell; Nehmé Saksouk; Teresa K Barth; Satoru Ide; Serge Urbach; Raymund J Wellinger; Reini F Luco; Axel Imhof; Jérôme Déjardin

doi:10.1126/sciadv.aav3673

SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres

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

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Heterochromatin / metabolism*
Histone Chaperones / metabolism
Histone-Lysine N-Methyltransferase / antagonists & inhibitors
Histone-Lysine N-Methyltransferase / deficiency
Histone-Lysine N-Methyltransferase / genetics
Histone-Lysine N-Methyltransferase / metabolism*
Humans
Methyltransferases / deficiency
Methyltransferases / genetics
Mice
Mice, Inbred C57BL
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism
RNA Interference
RNA, Small Interfering / metabolism
Repressor Proteins / deficiency
Repressor Proteins / genetics
Telomere / metabolism*
Telomere Shortening*
Telomeric Repeat Binding Protein 2 / metabolism
X-linked Nuclear Protein / metabolism

Substances

Heterochromatin
Histone Chaperones
RNA, Small Interfering
Repressor Proteins
Telomeric Repeat Binding Protein 2
Suv39h1 protein, mouse
Methyltransferases
Histone-Lysine N-Methyltransferase
SETDB1 protein, human
SETDB1 protein, mouse
X-linked Nuclear Protein