Promoters and transcription factors

Promoters & Core Elements - The Genetic "On" Switch

• Promoter: A DNA region upstream (5') of a gene where RNA polymerase II binds to initiate transcription. Not transcribed.
• Core Elements: Consensus sequences that act as binding sites.
  • TATA Box: At position -25 to -35. Binds TATA-binding protein (TBP) of TFIID, positioning RNA Pol II.
  • CAAT Box: At -70 to -80. Binds general transcription factors.
  • GC Box: Binds specific transcription factors (e.g., Sp1).

⭐ Mutations in promoter regions, like the TATA box, can abolish transcription initiation. This is a mechanism in some forms of β-thalassemia, where β-globin gene expression is severely reduced.

Transcription Factors - The Protein Regulators

• Function: Proteins that bind specific DNA sequences (enhancers, silencers) to modulate the rate of transcription from a gene's promoter.
• Types:
  • General (Basal) TFs: Position RNA polymerase II at the start of a protein-coding sequence and then release the polymerase to transcribe. E.g., TFIID, TFIIB.
  • Specific TFs: Bind to distant control elements (enhancers, silencers) to regulate gene expression in response to specific signals (e.g., hormones) or in a tissue-specific manner.
• Structural Domains:
  • DNA-Binding Domain: Recognizes & binds specific DNA motifs (e.g., Zinc finger, Leucine zipper, Helix-loop-helix).
  • Activation/Repressor Domain: Interacts with co-activators or co-repressors to modulate chromatin structure and recruit RNA polymerase.

⭐ The tumor suppressor protein p53 is a critical transcription factor that responds to DNA damage by halting the cell cycle and inducing apoptosis. Mutations in its TP53 gene are found in over 50% of human cancers.

Enhancers & Silencers - The Volume Knob

• Enhancers: Regulatory DNA sequences that, when bound by specific proteins (activators), ↑ the transcription of a gene.
• Silencers: DNA sequences that bind transcription regulation factors (repressors) to ↓ or suppress gene transcription.
• Key Features:
  • Can be located thousands of base pairs upstream or downstream from the gene they regulate, or within an intron.
  • Function in a position and orientation-independent manner.
  • Mechanism involves DNA bending, allowing transcription factors bound to a distant enhancer to interact with the RNA polymerase II complex at the promoter.

⭐ Tissue-specific gene expression is often controlled by the presence of specific transcription factors that bind to enhancer or silencer elements, effectively turning genes ON or OFF in different cell types.

Clinical Tie-ins - Faulty Gene Switches

• Promoter Mutations: Alterations in key sequences (e.g., TATA box, CAAT box) can abolish or reduce transcription.
  • Example: Certain forms of β-thalassemia arise from mutations in the β-globin gene promoter, leading to deficient globin synthesis.
• Transcription Factor (TF) Dysregulation:
  • Genetic Mutations: Defects in TF genes can cause developmental anomalies (e.g., HOXD13 mutations → synpolydactyly).
  • Autoantibodies: In SLE, autoantibodies can target TFs or associated proteins (e.g., anti-Smith, anti-Ro, anti-La), disrupting their function.
• Oncogenesis: Many oncogenes and tumor suppressors are TFs.
  • p53: A critical tumor suppressor TF; its mutation is a key step in many cancers.

⭐ Mutations in the TP53 gene are the single most common genetic event in human cancers. A faulty p53 fails to activate genes for cell cycle arrest or apoptosis, permitting unchecked proliferation of damaged cells.

High-Yield Points - ⚡ Biggest Takeaways

• Promoters (e.g., TATA box, CAAT box) are cis-acting DNA sequences upstream of a gene where RNA polymerase II binds to initiate transcription.
• Transcription factors are trans-acting proteins that bind to promoters or enhancers/silencers to regulate transcription.
• Enhancers are DNA sites that increase transcription; silencers decrease it. They can be located far from the gene they regulate.
• Mutations in promoter regions can significantly reduce or prevent gene expression.
• Common DNA-binding motifs in transcription factors include zinc fingers, leucine zippers, and helix-loop-helix domains.