| RBPSUH, also termed RBPJ, CSL, or CBF1, is a sequence‑specific DNA‑binding transcription factor of the CSL family that acts as a nuclear effector of canonical Notch signaling and regulates gene expression independently of Notch in multiple vertebrate tissues. The protein contains an N‑terminal domain, a central beta‑trefoil domain, and a C‑terminal domain, which together create the surface that recognizes a GTGGGAA‑type consensus motif and provide docking sites for corepressors, the Notch intracellular domain, and coactivators. RBPJK occupies its cognate motifs on chromatin in the absence of ligand‑activated Notch and associates with corepressor complexes that include SHARP and histone deacetylases, directing histone H3 lysine 27 deacetylation and maintaining Notch‑responsive promoters and enhancers in a transcriptionally repressed state. Ligand‑induced cleavage of Notch receptors generates the Notch intracellular domain, which binds RBPJK through its RAM and ankyrin regions and recruits Mastermind‑like coactivators to form an activation complex that stabilizes RBPJK on DNA, attracts histone acetyltransferases, promotes H3K27 acetylation, and increases RNA polymerase II engagement at target loci. This cofactor exchange at prebound RBPJK sites correlates with conversion of repressed elements into transcriptionally active regulatory regions and with increased transcription of classical Notch targets such as Hes and Hey family genes, along with additional context‑dependent targets identified by genome‑wide analyses. RBPJK binding demarcates clusters of regulatory elements with dynamic H3K27 acetylation cycles that correlate with pulsed Notch activity and with temporal changes in the amplitude of Notch‑dependent transcriptional responses. Genome‑wide maps show that RBPJK binds extensively beyond classical Notch‑responsive genes, including sites detected under conditions with minimal Notch signaling, where RBPJK occupies regulatory regions together with other transcriptional regulators and marks components of cell type‑specific transcriptional networks. RBPJK‑dependent Notch signaling regulates gene expression programs that associate with proliferation, survival, and differentiation, including programs required for T‑cell development and progenitor maintenance. In T‑cell acute lymphoblastic leukemia and other Notch‑driven cancers, NOTCH1 and RBPJK form chromatin‑bound complexes at regulatory elements near genes that are expressed and support leukemic cell properties, and RBPJK serves as the direct DNA‑binding platform for Notch‑dependent transcriptional regulation in these settings and has potential as a target for pharmacological modulation of Notch signaling. |
