GeneticsTier 1Medical Sciences concept

Molecular biology basics - DNA packaging (histones, nucleosomes) and translation machinery (tRNA, rRNA, ribosome)

Core concept

Packaging

2 m of DNA into a ~10 micrometre nucleus - ~10,000-fold compaction
Nucleosome = 147 bp wrapped 1.65 turns around a histone octamer
- Octamer = 2 x (H2A, H2B, H3, H4); H1 is the linker, binds entry/exit DNA and stacks nucleosomes
- "Beads on a string" (11 nm) -> 30 nm fibre -> loops on a scaffold -> chromatid
Histones are lysine/arginine-rich -> positively charged -> bind the negatively charged phosphate backbone
Euchromatin = open, transcribed; heterochromatin = condensed, silent

Epigenetic control - the exam's angle

Histone ACETYLATION (HAT) -> neutralises lysine charge -> loosens DNA -> ACTIVATES transcription
Histone DEACETYLATION (HDAC) -> condenses -> SILENCES
DNA methylation at CpG islands -> silencing (DNMTs); methylation of histone tails can activate or silence depending on residue (H3K4me3 active, H3K9me3/H3K27me3 repressive)
Non-coding RNA, imprinting and X-inactivation (XIST) use the same machinery

Central dogma

DNA -> (transcription, RNA polymerase II) -> pre-mRNA -> (splicing, 5' cap, poly-A tail) -> mRNA -> (translation, ribosome) -> protein
RNA uses uracil where DNA uses thymine; RNA is single-stranded with ribose

Translation

mRNA carries the code in triplet codons; 64 codons, 20 amino acids -> degenerate but unambiguous
- AUG = start = methionine; UAA, UAG, UGA = stop
tRNA - adaptor: anticodon pairs with the codon, and the 3' CCA end carries the cognate amino acid
- Charged by aminoacyl-tRNA synthetase (one per amino acid) - ATP-dependent, the proofreading step that sets fidelity
- Wobble at the third base allows one tRNA to read several codons
rRNA - catalytic and structural core; the peptidyl transferase centre is rRNA, not protein - a ribozyme
- Eukaryote 80S = 60S + 40S; prokaryote 70S = 50S + 30S
Three ribosomal sites: A (aminoacyl - incoming), P (peptidyl - growing chain), E (exit)
Elongation: codon recognition -> peptide bond -> translocation (EF-2/EF-G, GTP)
Termination at a stop codon by release factors
Post-translational: folding (chaperones), glycosylation, cleavage, phosphorylation; misfolded protein -> ubiquitin-proteasome degradation

Antibiotics target the prokaryotic ribosome - the difference in subunits is the selectivity

Site	Drugs
30S	Aminoglycosides (misreading, irreversible), tetracyclines (block A-site tRNA)
50S	Macrolides, clindamycin, linezolid (blocks initiation complex), chloramphenicol, streptogramins

Aminoglycosides also cause read-through of premature stop codons - the origin of nonsense-suppression strategies in class I CFTR and Duchenne mutations

Drugs acting on chromatin and translation

HDAC inhibitors - vorinostat, romidepsin (cutaneous T-cell lymphoma); valproate is a weak HDAC inhibitor
Hypomethylating agents - azacitidine, decitabine (DNMT inhibition) in MDS and AML
EZH2 inhibitor tazemetostat (follicular lymphoma); BET inhibitors in trials
Antisense oligonucleotides and siRNA act on mRNA - nusinersen (SMA), inotersen/patisiran (ATTR), inclisiran (PCSK9)
mRNA vaccines deliver the template directly to host ribosomes

Disease mechanisms

Mitochondrial disease - mtDNA encodes its own tRNAs and rRNAs; MELAS = m.3243A>G in tRNA-Leu
Diamond-Blackfan anaemia - ribosomal protein genes (ribosomopathy); Shwachman-Diamond (SBDS)
Charcot-Marie-Tooth - aminoacyl-tRNA synthetase mutations (GARS, YARS)
Imprinting - Prader-Willi (paternal 15q11-13) vs Angelman (maternal); Beckwith-Wiedemann
Anti-synthetase syndrome - anti-Jo-1 is an antibody against histidyl-tRNA synthetase -> myositis, ILD, mechanic's hands
Anti-histone antibody -> drug-induced lupus; anti-dsDNA -> SLE
Diphtheria toxin and Pseudomonas exotoxin A ADP-ribosylate EF-2 -> arrest elongation

3 more sections, plus exam facts

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