Reciprocal regulation of DBC1 and Chk2 functions in the DNA damage response

Human DBC1 (Deleted in Breast Cancer 1; KIAA1967; CCAR2) is a nuclear protein with controversial effects on cancer cells and with important roles in the regulation of apoptosis, transcription and histones modifications. Previously, we reported that, in response to DNA damage, ATM and ATR phosphorylate DBC1 on T454, promoting the inhibition of the NAD+ dependent deacetylase SIRT1 and, finally, inducing p53 acetylation and apoptosis. We deepen characterized the molecular mechanism by which DBC1 inhibits SIRT1 and found that, beside ATM/ATR, the DBC1-dependent inhibition of SIRT1 requires also the checkpoint kinase Chk2 and the 11S proteasome activator REGγ. Specifically, in response to etoposide Chk2 phosphorylates REGγ promoting DBC1-REGγ interaction, thus increasing DBC1-SIRT1 binding and SIRT1 inhibition. In addition, we report that, upon DNA damage, the catalytic activity of Chk2 is modulated, by DBC1 with a final impact on DNA double strand breaks repair. Indeed, in response to etoposide, DBC1 favors Chk2 homodimerization and activation, which leads to KAP1 phosphorylation and DNA repair promotion. Therefore, we reveal a new physical and functional crosstalk among DBC1, SIRT1, Chk2 and REGγ, giving novel insights on their role in the DNA damage response.