Magni Martina, Ruscica Vincenzo, Buscemi Giacomo, Kim Ja-Eun, Nachimuthu Benjamin Tamilselvan, Fontanella Enrico, Delia Domenico, Zannini Laura
Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Department of Biosciences, University of Milan, 20133 Milan, Italy.
Nucleic Acids Res. 2014 Dec 1;42(21):13150-60. doi: 10.1093/nar/gku1065. Epub 2014 Oct 31.
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.
人类DBC1（乳腺癌缺失基因1；KIAA1967；CCAR2）是一种与细胞凋亡、转录和组蛋白修饰调控相关的蛋白质。在DNA损伤时，DBC1在苏氨酸454位点被ATM/ATR磷酸化，这种修饰增强了它与SIRT1的抑制性相互作用，导致p53乙酰化和p53依赖性细胞凋亡。在此，我们报告在DNA损伤反应（DDR）中，DBC1对SIRT1的抑制作用也依赖于Chk2，Chk2是一种转导激酶，在DNA损伤时被ATM激活，并参与DNA损伤信号的扩散。事实上，我们发现Chk2失活会减少DBC1与SIRT1的结合，从而阻止p53乙酰化和DBC1诱导的细胞凋亡。这些事件是由Chk2介导的11S蛋白酶体激活剂REGγ在丝氨酸247位点的磷酸化所介导的，这增加了REGγ与DBC1的相互作用并抑制了SIRT1。总的来说，我们的结果阐明了DBC1依赖性抑制SIRT1的潜在机制，并首次将Chk2和REGγ与ATM-DBC1-SIRT1轴联系起来。
