Fig. 7: Regulation of BRCA1 and BRCA2 expression during the cell cycle and in response to DNA damage or inhibitor treatment.
From: BRCA1 and BRCA2 gene expression: p53- and cell cycle-dependent repression requires RB and DREAM
Expression of BRCA1 and BRCA2 is primarily regulated through a shared mechanism. A During G0, transcription is repressed by DREAM and RB:E2F repressor complexes binding to E2F promoter sites. In S/G2 phases, the loss of these repressor complexes allows activating E2Fs to bind the promoters, thereby promoting gene expression. B Following DNA damage, the same complexes mediate downregulation of BRCA1 and BRCA2. DREAM and RB:E2F repressor complexes are formed when cyclin/CDK complexes are inhibited by p21, whose expression is induced by p53 activation. Thus, p53 indirectly represses BRCA1 and BRCA2 transcription via p21-mediated CDK inhibition. In a therapeutic context, small molecule CDK4/6 inhibitors such as ribociclib, palbociclib, and abemaciclib can functionally mimic p21 to suppress BRCA1 and BRCA2 expression. The figure was created using BioRender.com.
