Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer

Raffaella Di Micco, Gabriele Sulli, Miryana Dobreva, Michalis Liontos, Oronza A. Botrugno, Gaetano Gargiulo, Roberto Dal Zuffo, Valentina Matti, Giovanni D'Ario, Erica Montani, Ciro Mercurio, William C. Hahn, Vassilis Gorgoulis, Saverio Minucci, Fabrizio D'Adda Di Fagagna

Research output: Contribution to journalArticlepeer-review

Abstract

Two major mechanisms have been causally implicated in the establishment of cellular senescence: the activation of the DNA damage response (DDR) pathway and the formation of senescence-associated heterochromatic foci (SAHF). Here we show that in human fibroblasts resistant to premature p16 INK4a induction, SAHF are preferentially formed following oncogene activation but are not detected during replicative cellular senescence or on exposure to a variety of senescence-inducing stimuli. Oncogene-induced SAHF formation depends on DNA replication and ATR (ataxia telangiectasia and Rad3-related). Inactivation of ATM (ataxia telangiectasia mutated) or p53 allows the proliferation of oncogene-expressing cells that retain increased heterochromatin induction. In human cancers, levels of heterochromatin markers are higher than in normal tissues, and are independent of the proliferative index or stage of the tumours. Pharmacological and genetic perturbation of heterochromatin in oncogene-expressing cells increase DDR signalling and lead to apoptosis. In vivo, a histone deacetylase inhibitor (HDACi) causes heterochromatin relaxation, increased DDR, apoptosis and tumour regression. These results indicate that heterochromatin induced by oncogenic stress restrains DDR and suggest that the use of chromatin-modifying drugs in cancer therapies may benefit from the study of chromatin and DDR status of tumours.

Original languageEnglish
Pages (from-to)292-302
Number of pages11
JournalNature Cell Biology
Volume13
Issue number3
DOIs
Publication statusPublished - Mar 2011

ASJC Scopus subject areas

  • Cell Biology

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