Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis

Martina Magni, Vincenzo Ruscica, Giacomo Buscemi, Ja Eun Kim, Benjamin Tamilselvan Nachimuthu, Enrico Fontanella, Domenico Delia, Laura Zannini

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)13150-13160
Number of pages11
JournalNucleic Acids Research
Volume42
Issue number21
DOIs
Publication statusPublished - Dec 1 2014

ASJC Scopus subject areas

  • Genetics

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