Start and stop codons

Genetic code

Start and stop codons

Features of the genetic code

• Unambiguous (Specific)
  • Each codon specifies only one amino acid.
  • Example: UUU always codes for Phenylalanine.
• Degenerate (Redundant)
  • Most amino acids are coded by multiple codons.
  • This protects against mutations; silent mutations often occur in the 3rd position (Wobble hypothesis). t
  • Exceptions: Only Methionine (AUG) and Tryptophan (UGG) are encoded by a single codon.
• Commaless / Non-overlapping
  • The code is read from a fixed starting point as a continuous sequence of bases without punctuation.
  • Altering the reading frame (e.g., via frameshift mutation) dramatically changes the protein product.
• Universal
  • The code is conserved throughout evolution (bacteria to humans).
  • Exception: Human mitochondria utilize a slightly different code (e.g., UGA codes for Tryptophan instead of Stop).

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Transcription

Regulation of transcription

• Promoter: DNA sequence where RNA polymerase II and general transcription factors (e.g., TFIID) bind.
  • TATA box (rich in A-T) usually located ~25 bp upstream.
  • CAAT box located ~75 bp upstream.
  • Mutation in the promoter results in a significant ↓ in the level of transcription.
• Enhancers: DNA sequences that increase the rate of transcription by binding activator proteins.
• Silencers: DNA sequences that decrease the rate of transcription by binding repressor proteins.
• Note: Enhancers and silencers can be located far upstream, downstream, or even within introns of the gene they regulate. t

Transcription factor

• Definition
  • Proteins that bind DNA to control the rate of transcription (DNA $\to$ mRNA).
• Key Structural Motifs (Classic USMLE Question)
  • Zinc Finger: Steroid receptors (Estrogen, Aldosterone, Cortisol), Thyroid hormone, Vit D, Vit A.
  • Helix-Turn-Helix: Homeobox (HOX) genes (developmental axis patterning).
  • Leucine Zipper: c-Myc, c-Jun, c-Fos (proto-oncogenes).
• Binding Sites
  • Promoters (e.g., TATA box): Located immediately upstream (-25 bp). Bind basal factors/RNA Pol II.
  • Enhancers/Silencers: Located anywhere (far upstream, downstream, or within introns). Regulate expression levels.
• Mechanism (Intracellular Receptors)
  • Lipid-soluble hormones (Steroids, T3/T4) cross membrane $\to$ bind cytosolic/nuclear receptor $\to$ complex enters nucleus $\to$ binds DNA via Zinc finger.
• Clinical Associations
  • HOX Mutations: Appendages in wrong locations (synpolydactyly t ). Altered by Retinoic Acid (teratogenic).
  • Li-Fraumeni: Mutation in p53 (a TF) $\to$ inability to arrest cell cycle/induce apoptosis.
  • PPAR drugs:
    • Glitazones $\to$ PPAR-$\gamma$ (Diabetes).
    • Fibrates $\to$ PPAR-$\alpha$ (Hypertriglyceridemia).

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Translation process

Initiation

• Initiator met-tRNA, eukaryotic IF2 (eIF2), and GTP bind to the small ribosomal subunit to form a preinitiation complex (initially a 43s preinitiation complex).
  • eIF2: a small G protein
    • Binds initiator met-tRNA (ternary complex) and forms the final initiation complex by hydrolyzing GTP to GDP
    • Reconverted to the GTP-bound form by the guanine nucleotide exchange factor eIF2B
• Kozak sequence: Eukaryotic consensus sequence around the start codon that enhances initiation efficiency. t

Elongation

• An aminoacyl-tRNA complex with eukaryotic elongation factor 1 (eEF1) hydrolyzes GTP, thereby releasing eEF1 and GDP and providing the energy for aminoacyl-tRNA to bind the A site (anticodon matches the codon of the mRNA).

Termination

• A release factor recognizes the stop codon, halts translation, and hydrolytically cleaves the peptidyl tRNA bonds (requires GTP), leading to release of the protein.