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Mutation

Mutation. دانشگاه علوم پزشكي وخدمات بهداشتي درماني تهران. Dr. Parvin Pasalar Tehran University of Medical Sciences. Mutation. Definition: An un- repaired damages to DNA Causes: It may be spontaneous or induced because of different agents Classifications:

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Mutation

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  1. Mutation دانشگاه علوم پزشكي وخدمات بهداشتي درماني تهران Dr. Parvin Pasalar Tehran University of Medical Sciences

  2. Mutation • Definition: Anun- repaired damagesto DNA • Causes: It may be spontaneousor induced because of different agents • Classifications: are classified on different basis • Their importance: Genetic Disease& raw material for the development

  3. Different Causes of mutations: Contrary to popular belief… Most DNA damage is caused by endogenousmutagens Estimated DNA damage/day in human cells SSBs ~50,000/day Depurinations ~10,000/day Deaminations ~600/day Oxidations ~2000/day Alkylations ~5000/day DSBs ~50-100/day -

  4. Classifications of Mutations 1- Can be spontaneous or induced 2- May be substitutions or frameshift 3- May occur in structural or regulatory sequences 4- May be small (point) or big 5- May have no or severe effect 6- Somatic or germinal

  5. Different Causes of Mutations • Biological (normal error rate in DNA metabolic processes) • Physical (Radiation) Sunlight • Chemical (Mutagens, Carcinogens) 1- Alkylating agents 2- Base analogues 3- intercalating agents 4- Different chemicals such as: a- Nitrous acid b- Hydroxylamine

  6. Different Type of DNA damages • 1- Double-strand breaks (DSBs) • 2- Single- strand breaks (SSBs) • 3- Base alteration / damage a: Oxidation b: Alkylations c: Hydrolysis depurination deaminations

  7. DNA Damage, Repair, and Consequences Damaging agent Consequences • In hibition of: • Replication • Transcription • Chromosome segregation • Mutation • Chromosome aberration Repair Process

  8. Can we detectMutagen: Ames Assay Bruce Nathan Ames Brith:1928 Ames test: 1970

  9. Repair دانشگاه علوم پزشكي وخدمات بهداشتي درماني تهران Dr. Parvin Pasalar Tehran University of Medical Sciences

  10. 4. Recombinational repair - multiple pathways - double strand breaks and interstrand cross-links Tolerance mechanisms - lesion bypass - recombination DNA Repair Pathways 1. Direct reversals 2. Excision repair a. Base excision repair (BER) b. Nucleotide excision repair (NER) • 3. Mismatch repair • - replication errors

  11. 1-Direct reversal: photoreactivation T T T T Visible light Damage Recognized: Thymine dimers 6-4 photoproduct Gene Products Required: Photolyase Related disease: Photolyase not yet found in placental mammals

  12. 2-Excision Repair Pathways • a. Base Excision Repair • damaged bases are removed as free bases • primarily responsible for removal of oxidative and alkylation damages • most genes in pathway are essential • thought to have an important role in aging • b. Nucleotide Excision Repair • damaged bases are removed as oligonucleotides • primarily responsible for removal of UV-induced damage and bulky adducts • also removes ~ 20% of oxidative damage • deficient in human disorders

  13. 2-Excision Repair Pathways BER NER DNA Ligase DNAP+ Ligase DNAP+ Ligase

  14. Genetics of NER in Humans 1- Xeroderma PigmentosumOccurrence: 1-4/106 population Sensitivity: sunlight Disorder: multiple skin disorders; malignancies of the skin neurological and ocular abnormalities Biochemical defect: early step of NER Genetic: seven genes (A-G), autosomal recessive

  15. Genetics of NER in Humans 2- Cockayne’s Syndrome Occurrence: 1 per/ 106 population Sensitivity: sunlight Disorder: arrested development, mental retardation, dwarfism, deafness, optic atrophy, intracranial calcifications Biochemical defect : NER Genetic: five genes (A, B and XPB, D & G) autosomal recessive

  16. 3- Mismatch Repair in E. coli : Decision between right & wrong (methyl-directed) Before replication both strands of GATC are methylated Shortly afte replication it is hemimethylated After a while it becomes fully methylated again

  17. MMR Mutations inHereditary Nonpolyposis Colon Cancer (HNPCC) • MMR mutations in 70% of families • Population prevalence 1: 2851 (15-74 years) • 18% of colorectal cancers under 45 years • 28% of colorectal cancers under 30 years

  18. Summary

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