Fig. 2: Dual role of cell identity safe-guarders.
From: The interplay of DNA damage, epigenetics and tumour heterogeneity in driving cancer cell fitness
(line 1) To control cell identity, BMI1 (a polycomb repressor complex 1 (PRC1) protein) increase monoubiquitinylation of H2AK119 to inhibit the transcription of differentiation-associated genes. To activate DNA repair, BMI1 ubiquitinylate histones next to DSB. It leads to local transcription inhibition and recruitment of (C-terminal binding protein) interacting protein (CtIP) to promote DNA end resection and homologous recombination (HR). (line2) To control cell identity, EZH2 (a PRC2 protein) increase H3K27me3 marks to inhibit the transcription of differentiation-associated genes. To activate DNA repair EZH2 promote HR though the downregulation of Schlafen11 gene expression (SLFN11, an DNA/RNA helicase), and increase H3K27me3 marks on histones neighboring the DSB to induce local transcription silencing. Moreover, EZH2 is also known to inhibit REV7, hence favoring the HR repair pathway choice. (line 3) To control cell identity, BRD4 (Bromodomain-containing protein 4) regulates the transcription of genes-related to stemness by promoting enhancer-promoter interaction. To activate DNA repair, BRD4 interact with BRG1 to increase histone eviction and bind to histones next to DSB favoring CtIP recruitment and HR repair activity. In addition, BARD4 binds super-enhancers with MED1 and TEAD, to promote the recruitment of Rad51 and DNA repair on high transcript loci (line 4) To control cell identity, ZEB1 (Zinc finger E-box binding homeobox 1) play as a major regulator of the epithelial-to-mesenchymal transition (EMT) program. To activate DNA repair, ZEB1 promote HR and inhibit Alt-EJ by regulating the gene expression of ATM and polθ. Moreover, ATM phosphorylation enhance ZEB1 interaction with USP7 and CHK1 to promote HR pathway activity. Created in BioRender. Mitoyan, L. (2025) https://BioRender.com/5je9jd0.
