title: Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer.
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.
authors.affiliation: IFOM Foundation - FIRC Institute of Molecular Oncology Foundation, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Di Micco
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sulli
authors.forename: Miryana
authors.initials: M
authors.lastname: Dobreva
authors.forename: Michalis
authors.initials: M
authors.lastname: Liontos
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.forename: Gaetano
authors.initials: G
authors.lastname: Gargiulo
authors.forename: Roberto
authors.initials: R
authors.lastname: dal Zuffo
authors.forename: Valentina
authors.initials: V
authors.lastname: Matti
authors.forename: Giovanni
authors.initials: G
authors.lastname: d'Ario
authors.forename: Erica
authors.initials: E
authors.lastname: Montani
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D006570:Heterochromatin / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D009857:Oncogenes; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering