ADN Flashcards
Acetylation in thyroid gland
Thyroid hormone receptors alter thyroid hormone synthesis by acetylation
Acetylation
Acetyl group added to lysine Relaxes chromatin Ups transcription
How do histones form Chromatin?
DNA loops twice around histone octamer (2x H2A, H2B, H3, H4) H1 binds to nucleosome and linker DNA condensing them into chromatin
Acetylation related diseases
Huntington: dysregulated acetylation were histone deacetylation may silence genes that should control Huntington’s protein leading to neuron cell death in striatum. Valproic acid hace effects inhibiting deacetylation
DNA Methylation
Promoted by CG islands Reduces transcription
Heterochromatin
Highly condensed NOT active for transcription Highly methylated
Inhibidores de síntesis de purinas
Azatioprina y 6 mercaptopurina Ribavirina y micofenolato
Euchromatin
Expressed DNA Less condense Histone acetylation
Drug induced lupus: Drugs Antibodies Symptoms
Drugs: hidralazine, procainamide, isoniazid
Anti-histone antibodies (95%)
Fever, joint pain, rash
Histone aminoacids
Lysine Arginine
Fármacos que bloquean la dihidrofolato reductasa Humanos Bacterias Hongos
Humanos: metrotexato Bacterias: trimetoprim Hongos: Pirimetamina
Fármacos que bloquean la conversión de carbamoil fosfato a ácidos orotico
Leflunamida bloquea la dihidroorotato deshidrogenasa inhibiendo síntesis de pirimidinas
Orotic Aciduria Enzyme deficiency Clinical findings Treatment
Defect in UMP synthase Buildup of orotic acid + loss of pyrimidines Autosomal recessive Orotic acid in urine + megaloblastic anemia + hypersegmented neutrophils with NO response to B12 or B9 + Growth retardation Treatment: Uridine —> Bypasses UMP synthase
Differential diagnosis for orotic aciduria
Orhithine transcarbamylase (OTC) deficiency Enzyme combines carbamoyl phosphate + ornithine to make citrulline in urea cycle Causes orotic aciduria however it also has high levels of ammonia and generates encephalopathy (baby with lethargy and coma)
Drug that inhibit dUMP to dMTP + enzyme
Enzyme: Thymidylate synthase Drug: 5-fluorouracil (5-FU)
Pyrimidine analog that mimics dCTP
Cytarabine: chemotherapy agent that inhibits DNA polymerase
Trimethoprim Sulfa action mechanism
Inhibits formation of thymidine (dTMP)
- Sulfonamide mimics PABA
- Trimethoprim inhibits dihydrofolate reductase
Folate trap
Folate vs B12 deficiency anemia
- Both are macrocytic anemias with hypersegmented neutrophils
- Both are caused by defective DNA synthesis –> Thymidine synthesis
- Both have high homocysteine levels
- Only B12 has high methymalonic acid levels
Purine precursors
- N: GAG –> glycine, glutamine, aspartato
- C: CO2, Tetrahidrofolato
- 5 ribose phosphate
Pyrimidines precursors
- N: glutamine and aspartate
- C: tetrahydrofolate and CP2
- ribose phospate
DNA Damage
DNA Repair Mechanisms
Single strand:
- Base excision: Recognise específico base errors ( deamination, oxidation, open rings)
- Nucleotide excision: Damage in multiple bases generated by UV radiation. Only G1.
- Mismatch repair: Damage in DNA match between strands. Backup if proofreading misses error. Only S and G2. Related to microsatelite stability.
Double Strand: Radiation
- Hologous end joining: Uses sister chromosome template.
- Non-homologous end joining: No template so it is highly prone to error.
Illness related to defects in DNA Repair
- Xeroderma pigmentosaum: nucleotide excision repair
- Lynch syndrome: mismatch repair. Microsatelite inestabilidad. Mutations in MLH1 and MSH2. Colon, endometrium, ovarian and skin cancer.
- Franconia anemia: homologous end joining. Mutation in DNA repair enzymes causes cells vulnerable to DNA cross links.
Ataxia telangiectasia: non-homologous end joining repair. 4 A’s.
