10/17 - DNA repair defects Flashcards
(37 cards)
Chromosomal instability at molecular level: GENOME NUMBER
Effect: POLYPLOIDY
Chromosomal instability at molecular level: GENOME STRUCTURE
Effect: LOSS OF HETEROZYGOSITY
Chromosomal instability at molecular level: CHROMOSOME NUMBER
Effect: ANEUPLOIDY
Chromosomal instability at molecular level: CHROMOSOME STRUCTURE
Effect:
- DICENTRIC
- TELOMERE LENGTH
- TRANSLOCATIONS
- FUSIONS
Chromosomal instability at molecular level: SEQUENCE INTEGRITY
Effect:
- BASEPAIR SUBSTITUTIONS
- DELETIONS & INSERTIONS
- METHYLATIONS
Chromosome Instability Causes: DEFECT IN CELL DIVISION
Effects:
- Polyploidy
- Aneuploidy
Chromosome Instability Causes: RECOMBINATION
Effect:
- Loss of heterozygosity
Chromosome Instability Causes: DNA Replication
Effects:
- Amplification
- Deletions & Insertions
- Basepair Substitutions
Chromosome Instability Causes: DNA Repair
Effects:
- Translocations
- Fusions
Chromosome Instability Causes: Dysregulation of Expression
Effect:
- Methylation
Chromosome Instability Causes: Attrition with Cell Proliferation
Effect:
- Telomere length
Chromosome Instability Causes
- Defects in cell division
- Recombination
- DNA replication
- DNA repair
- Attrition with cell proliferation
- Dysregulation of expression
Environmental DNA Damage
1) UV
2) X-rays
3) Heat generated hydrocarbons
4) Food additives
5) Job related exposures
6) Chemotherapeutic agents
*Repair mechanisms for environmental DNA damage:
1) Nucleotide excision repair
2) Double-strand break repair
3) Interstrand crosslink repair
Spontaneous DNA Damage
1) Hydrolysis
2) Reactive oxygen species
3) Nitric oxide
4) Methylation
5) Lipid peroxidation
*Repair mechanisms for spontaneous DNA damage:
1) Base excision repair (&single-strand break repair)
2) Methyl transferase
DNA repair: Why?
- Repository of hereditary information
- Blueprint for operation of individual cells
- Only biomolecule that is repaired rather than replaced
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”
Consequences of not repairing DNA damage (cell)
- Errors in division
- Chromosomal aberrations
- Apoptosis
- Senescence
- Mutations
Consequences of not repairing DNA damage (organism)
- Xeroderma pigmentosum
- Cockayne syndrome
- Trichothiodystrophy
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
*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
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?
Xeroderma Pigmentosum
- Affected genome maintenance system: Nucleotide excision repair (NER)
- Genome Instability: Point mutations
- Phenotype: UV-induced skin cancer
