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

Item Type:Article
Title:Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer
Creators Name:Di Micco, R. and Sulli, G. and Dobreva, M. and Liontos, M. and Botrugno, O.A. and Gargiulo, G. and dal Zuffu, R. and Matti, V. and d'Ario, G. and Montani, E. and Mercurio, C. and Hahn, W.C. and Gorgoulis, V. and Minucci, S. and d'Adda di Fagagna, F.
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.
Keywords:Apoptosis, Cell Aging, Chromatin, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, DNA Replication, Fluorescence Microscopy, Heterochromatin, Histone Deacetylase Inhibitors, Neoplasm Transplantation, Neoplasms, Oncogenes, Plasmids, Small Interfering RNA, Tumor Cell Line, Animals, Mice
Source:Nature Cell Biology
Publisher:Nature Publishing Group
Page Range:292-302
Date:March 2011
Official Publication:https://doi.org/10.1038/ncb2170
PubMed:View item in PubMed

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