Transcription Factors

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Prompt

Roles of Transcription Factors in the Preinitiation Complex (PIC): The preinitiation complex is a multi-protein assembly critical for recruiting RNA polymerase II (RNAPII) to gene promoters and initiating transcription. Each transcription factor (TF) plays distinct roles: TFIID Role: Serves as the foundational scaffold. Contains the TATA-binding protein (TBP), which recognizes and binds the TATA box in the promoter. Other subunits (TAFs) recognize alternative promoter elements (e.g., Initiator or downstream promoter elements). Chemistry: TBP distorts DNA via minor groove interactions, bending the DNA to facilitate PIC assembly. TAFs mediate interactions with acetylated histones or modified chromatin. Order: First to bind the promoter. TFIIA Role: Stabilizes TFIID-DNA interactions, preventing dissociation. Enhances promoter recognition by counteracting repressors. Chemistry: Binds to TFIID and DNA, forming a stable ternary complex. TFIIB Role: Bridges TFIID and RNAPII. Positions RNAPII at the transcription start site (TSS) by binding both the promoter and polymerase. Chemistry: Binds DNA upstream of the TATA box and interacts with RNAPII to ensure proper orientation. Order: Recruited after TFIID and TFIIA. RNA Polymerase II (RNAPII) Role: Catalyzes RNA synthesis. Its C-terminal domain (CTD) undergoes phosphorylation to transition from initiation to elongation. Chemistry: Brought to the promoter via interactions with TFIIB and TFIIF. TFIIF Role: Escorts RNAPII to the PIC. Stabilizes RNAPII binding and may suppress non-specific DNA interactions. Chemistry: Binds RNAPII and TFIIB, enhancing polymerase recruitment. TFIIH Role: Dual enzymatic activity: Helicase: Unwinds DNA using ATP hydrolysis (via subunits XPB/XPD) to create a transcription bubble. Kinase: Phosphorylates the CTD of RNAPII, signaling promoter escape. Chemistry: ATP-dependent DNA unwinding and kinase-mediated phosphorylation (Ser5 on CTD). Order: Joins late in PIC assembly, critical for initiation. TFIIE Role: Regulates TFIIH activity. Enhances helicase function and recruits chromatin remodelers. Chemistry: Interacts with TFIIH to modulate ATPase/helicase activity. Mediator Complex Role: Acts as a coactivator, bridging enhancer-bound activators/repressors and the PIC. Integrates regulatory signals. Chemistry: Binds transcription factors (e.g., p53, nuclear receptors) and RNAPII, facilitating conformational changes in the PIC. Assembly Order and Collaboration: TFIID binds the promoter. TFIIA stabilizes TFIID-DNA interactions. TFIIB links TFIID to RNAPII-TFIIF. TFIIH and TFIIE join, enabling DNA unwinding and CTD phosphorylation. Mediator facilitates communication between regulatory proteins and the PIC. Key Interactions and Outcomes: DNA Recognition: TFIID (TBP/TAFs) anchors the PIC to the promoter. Polymerase Recruitment: TFIIB and TFIIF position RNAPII at the TSS. DNA Unwinding: TFIIH helicase activity prepares the template strand. Transition to Elongation: TFIIH-mediated CTD phosphorylation releases RNAPII from the promoter. Aberrancies (Brief): Mutations in TBP impair promoter recognition. Defective TFIIH helicase/kinase (e.g., in Xeroderma pigmentosum) blocks initiation. Loss of Mediator disrupts enhancer-promoter communication, reducing transcription. This orchestrated assembly ensures precise regulation of gene expression, integrating basal transcription machinery with regulatory signals.