Journal Article

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

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

2011

Overview

Different mechanisms have been implicated in the induction of senescence. Two of these mechanisms, the DNA damage response, which induces a replicative checkpoint, and the formation of heterochromatic foci, which leads to transcriptional repression, are found to act together in oncogene-expressing cells. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/1427/2566 / 631/67 / 631/80/509 / Animals / Apoptosis / Ataxia / Biomedical and Life Sciences / Cancer / Cancer Research / Cancer therapies / Cell Biology / Cell cycle / Cell Line, Tumor / Cellular Senescence / Chromatin / Chromatin - metabolism / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / Deoxyribonucleic acid / Development and progression / Developmental Biology / DNA / DNA Damage / DNA Replication / Fibroblasts / Genetic aspects / Health aspects / Heterochromatin - genetics / Histone Deacetylase Inhibitors - pharmacology / Humans / Inactivation / Life Sciences / Mice / Microscopy / Microscopy, Fluorescence - methods / Neoplasm Transplantation / Neoplasms - metabolism / Oncogenes / Oncology / Physiological aspects / Plasmids - metabolism / Radiation / Risk factors / RNA, Small Interfering - metabolism / Senescence / Stem Cells / Tumors