title: Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis.
abstract: Human DBC1 (Deleted in Breast Cancer 1; KIAA1967; CCAR2) is a protein implicated in the regulation of apoptosis, transcription and histone modifications. Upon DNA damage, DBC1 is phosphorylated by ATM/ATR on Thr454 and this modification increases its inhibitory interaction with SIRT1, leading to p53 acetylation and p53-dependent apoptosis. Here, we report that the inhibition of SIRT1 by DBC1 in the DNA damage response (DDR) also depends on Chk2, the transducer kinase that is activated by ATM upon DNA lesions and contributes to the spreading of DNA damage signal. Indeed we found that inactivation of Chk2 reduces DBC1-SIRT1 binding, thus preventing p53 acetylation and DBC1-induced apoptosis. These events are mediated by Chk2 phosphorylation of the 11S proteasome activator REGγ on Ser247, which increases REGγ-DBC1 interaction and SIRT1 inhibition. Overall our results clarify the mechanisms underlying the DBC1-dependent SIRT1 inhibition and link, for the first time, Chk2 and REGγ to the ATM-DBC1-SIRT1 axis.
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Magni
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ruscica
authors.affiliation: Department of Biosciences, University of Milan, 20133 Milan, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Buscemi
authors.affiliation: Department of Pharmacology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Ja-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy.
authors.forename: Benjamin Tamilselvan
authors.initials: BT
authors.lastname: Nachimuthu
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Fontanella
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy laura.zannini@istitutotumori.mi.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy laura.zannini@istitutotumori.mi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Zannini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis; D001324:Autoantigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; C527450:CCAR2 protein, human; C099558:Ki antigen; D064447:Checkpoint Kinase 2; D046988:Proteasome Endopeptidase Complex; D056564:Sirtuin 1