Download - genome Instability
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Genomic instability & DNA
repair I
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Molecular Medicine
• Identifying the molecular basis of human disease
• Translating molecular defects into clinical symptoms
• Understanding molecular basis of human disease
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Plan• DNA damage and genotoxic agents
• Effects on cells
• DNA repair
• Clinical implications of defective DNA repair - genomic instability
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DNA damage• A large number of DNA lesions occur in our cells• Estimates: 1,000 - 1,000,000 DNA lesions / cell /
day• How do cells cope with these lesions?• DNA - the only molecule in our body that is
repaired• The rest are replaced
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Sources of DNA damage
• Endogenous
• Free radicals
• Exogenous
• Genotoxic agents
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Genotoxic agents• Radiation
– Ionizing• Particles (, ) and rays (X- and )
– Non-ionizing• UV light
• Chemical agents– Alkylating agents, acridine etc.
• Biological agents– Viruses
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Types of DNA damage caused by genotoxic agents
apurinic site (alkylating agents)
intercalation (acridine)
alkylation (alkylationg agents)
adducts (many chemicals)
pyrimidine dimers (UV radiation)
double-strand breaks (ionizing radiation)
interstrand cross-links (alkylating agents)
intrastrand cross-links (alkylating agents)
apyrimidinic site (alkylating agents)
single-strand break (ionizing & UV rad.)
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DNA damage response• Network of cellular mechanisms that
sense, signal and repair DNA damage• Linked with cell cycle checkpoint
mechanisms• Linked with mechanisms that regulate
apoptosis
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DNA damage response (DDR)
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How is DDR regulated?
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Clinical implications• Low fidelity repair - Genetic defects in cellular
mechanisms responsible for DNA damage response • Sensitivity to genotoxic stress
– When individual exposed to radiation or chemicals in cancer therapy
• Long term effects– Cancer predisposition– Premature ageing– Immunodeficiency– Infertility
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Clinical implications• Low fidelity repair - Genetic
defects in cellular mechanisms responsible for DNA damage response
• Sensitivity to genotoxic stress– When individual exposed to
radiation or chemicals in cancer therapy
• Long term effects– Cancer predisposition– Premature ageing– Immunodeficiency– Infertility
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11_21.jpg
Depurination and deamination
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11_21_2.jpgA thymidine dimer
How chemical changecauses a mutation
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DNA repair mechanisms• BER (base excision repair)• NER (nucleotide excision repair)
– Global NER
– Transcription coupled NER
• MMR (mismatch repair)• DSB repair (repair of DNA double strand breaks)
– Homologous recombination (HR)
– Non-homologous end-joining (NHEJ)
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NER• Two types
– Global genomic NER– Transcription coupled NER
• Steps – Damage recognition– Binding of a multi-protein complex at the damaged site– Double incision of the damaged strand– Removal of the damage-containing oligonucleotide from between
the two nicks– Filling in of the resulting gap by a DNA polymerase– Ligation
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Proteins involved in NER
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Global genome NER
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Transcription coupled NER
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Clinical consequences of dysfunctional NER
• Xeroderma pigmentosum (XP) (MIM 278700)
• Cockayne’s syndrome (CS) (MIM 216400)
• Trichothiodystrophy (TTD) (MIM 601675)
• Complementation groups: 7 XP, 2 CS & 2 TTD
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XP• Seven complementation
groups: XPA - XPG I.e. seven genes identified
• Symptoms: light sensitivity, pigmentation irregularities
• Frequent neurological defects
• High incidence of early onset skin cancer
• Elevated frequency of other forms of cancer
• Premature ageing
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CS• Abnormal and slow growth• Dwarfism• Skin photosensitivity, thin dry hair• Facial and limb abnormalities• Neurological abnormalities• Early death due to neurodegeneration • Premature ageing in some tissues• Molecular genetics
– Two complementation groups (CSA & CSB)– CSA - ERCC8 (5q11)– CSB - ERCC6 (10q11)
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TTD
• Sulfur deficient brittle hair and nails• Facial abnormalities and short stature• Ichthyosis (fish-like scales on the skin)• Light sensitivity in some cases• Premature ageing in some tissues• Molecular genetics
– XPD– TTD-A
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MMR
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Clinical consequences of defective MMR
• HNPCC - Hereditary Nonpolyposis Colon Cancer