Flashcards in 10/17 - DNA repair defects Deck (37)
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1
Chromosomal instability at molecular level: GENOME NUMBER
Effect: POLYPLOIDY
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Chromosomal instability at molecular level: GENOME STRUCTURE
Effect: LOSS OF HETEROZYGOSITY
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Chromosomal instability at molecular level: CHROMOSOME NUMBER
Effect: ANEUPLOIDY
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Chromosomal instability at molecular level: CHROMOSOME STRUCTURE
Effect:
- DICENTRIC
- TELOMERE LENGTH
- TRANSLOCATIONS
- FUSIONS
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Chromosomal instability at molecular level: SEQUENCE INTEGRITY
Effect:
- BASEPAIR SUBSTITUTIONS
- DELETIONS & INSERTIONS
- METHYLATIONS
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Chromosome Instability Causes: DEFECT IN CELL DIVISION
Effects:
- Polyploidy
- Aneuploidy
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Chromosome Instability Causes: RECOMBINATION
Effect:
- Loss of heterozygosity
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Chromosome Instability Causes: DNA Replication
Effects:
- Amplification
- Deletions & Insertions
- Basepair Substitutions
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Chromosome Instability Causes: DNA Repair
Effects:
- Translocations
- Fusions
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Chromosome Instability Causes: Dysregulation of Expression
Effect:
- Methylation
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Chromosome Instability Causes: Attrition with Cell Proliferation
Effect:
- Telomere length
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Chromosome Instability Causes
- Defects in cell division
- Recombination
- DNA replication
- DNA repair
- Attrition with cell proliferation
- Dysregulation of expression
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Environmental DNA Damage
1) UV
2) X-rays
3) Heat generated hydrocarbons
4) Food additives
5) Job related exposures
6) Chemotherapeutic agents
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*Repair mechanisms for environmental DNA damage:
1) Nucleotide excision repair
2) Double-strand break repair
3) Interstrand crosslink repair
15
Spontaneous DNA Damage
1) Hydrolysis
2) Reactive oxygen species
3) Nitric oxide
4) Methylation
5) Lipid peroxidation
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*Repair mechanisms for spontaneous DNA damage:
1) Base excision repair (&single-strand break repair)
2) Methyl transferase
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DNA repair: Why?
- Repository of hereditary information
- Blueprint for operation of individual cells
- Only biomolecule that is repaired rather than replaced
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Effort dedicated to DNA repair
- >150 proteins dedicated to DNA repair
~3X as many proteins regulate the DNA damage response
~2% of the genome is dedicated to maintaining genome integrity
- DNA repair proteins are "housekeeping proteins"
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Consequences of not repairing DNA damage (cell)
- Errors in division
- Chromosomal aberrations
- Apoptosis
- Senescence
- Mutations
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Consequences of not repairing DNA damage (organism)
- Xeroderma pigmentosum
- Cockayne syndrome
- Trichothiodystrophy
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Li-Fraumeni Syndrome
- Caused by a mutation in p53
- Osteosarcoma
- Soft tissue sarcoma
- Breast cancer
- Brain tumors
- Adrenocortical carcinoma
- Leukemia
- T cell lymphoma
- Expression of constitutively active p53 protects against cancer but causes premature aging
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*General principles of DNA repair
1) Recognize the DNA Damage
- Endogenous DNA damage (small/subtle, co-evolved, dedicated enzymes)
- Environmental DNA damage (larger/alter DNA structure, rapid adaptation, generalized systems)
2) Remove the damage
3) Replace coding information
4) Restore the integrity of the phosphate backbone
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Defects in DNA glycosylases: Phenotype associated w/ defect in mice and humans
- Mice: Defects in DNA glycosylases: none, but defects in core proteins = embryonic lethal
- Humans: Polymorphisms related to cancer risk?
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Xeroderma Pigmentosum
- Affected genome maintenance system: Nucleotide excision repair (NER)
- Genome Instability: Point mutations
- Phenotype: UV-induced skin cancer
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Cockayne Syndrome
- Affected genome maintenance system: Transition-coupled Nucleotide excision repair (NER)
- Genome Instability: Apoptosis
- Phenotype: Premature Aging
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Trichothiodystrophy
- Affected genome maintenance system: Transition-coupled Nucleotide excision repair (NER)
- Genome Instability: Apoptosis
- Phenotype: Premature Aging
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Ataxia Telanglectasia
- Affected genome maintenance system: DSB-R and checkpoint
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Leukemias and lymphomas
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AT-like disorder
- Affected genome maintenance system: DSB-R
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Ataxia
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Nijmegen breakage syndrome
- Affected genome maintenance system: DSB-R and checkpoint
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Lymphomas
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