SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres

• Published in: Science advances Vol. 5; no. 5; p. eaav3673
• Main Authors: Gauchier, Mathilde, Kan, Sophie, Barral, Amandine, Sauzet, Sandrine, Agirre, Eneritz, Bonnell, Erin, Saksouk, Nehmé, Barth, Teresa K., Ide, Satoru, Urbach, Serge, Wellinger, Raymund J., Luco, Reini F., Imhof, Axel, Déjardin, Jérôme
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 01.05.2019; American Association for the Advancement of Science
• Subjects: Animals; Biochemistry, Molecular Biology; Cancer; 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; Life Sciences; Methyltransferases - deficiency; Methyltransferases - genetics; Mice; Mice, Inbred C57BL; Molecular biology; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Repressor Proteins - deficiency; Repressor Proteins - genetics; RNA Interference; RNA, Small Interfering - metabolism; SciAdv r-articles; Telomere - metabolism; Telomere Shortening; Telomeric Repeat Binding Protein 2 - metabolism; X-linked Nuclear Protein - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aav3673

Atypical heterochromatin forms on telomeres and correlates with ALT activities. 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.