SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres

Mathilde Gauchier , Sophie Kan , Amandine Barral , Sandrine Sauzet (1) , Eneritz Agirre , Erin Bonnell , Nehmé Saksouk (2) , Teresa Barth , Satoru Ide , Serge Urbach (3) , Raymund Wellinger , Reini F Luco (2) , Axel Imhof (4) , Jérôme Déjardin (2)

1 BIOM - Biologie intégrative des organismes marins
2 IGH - Institut de génétique humaine
3 IGF - Institut de Génomique Fonctionnelle
4 CIPSM - Center for Integrated Protein Science

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.

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire; Biologie moléculaire

Mathilde Gauchier, Sophie Kan, Amandine Barral, Sandrine Sauzet, Eneritz Agirre, et al.. SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres. Science Advances , 2019, 5 (5), pp.eaav3673. ⟨10.1126/sciadv.aav3673⟩. ⟨hal-02350110⟩