Flashcards in 10/17 - DNA repair defects Deck (37)
Loading flashcards...
1
Chromosomal instability at molecular level: GENOME NUMBER
Effect: POLYPLOIDY
2
Chromosomal instability at molecular level: GENOME STRUCTURE
Effect: LOSS OF HETEROZYGOSITY
3
Chromosomal instability at molecular level: CHROMOSOME NUMBER
Effect: ANEUPLOIDY
4
Chromosomal instability at molecular level: CHROMOSOME STRUCTURE
Effect:
- DICENTRIC
- TELOMERE LENGTH
- TRANSLOCATIONS
- FUSIONS
5
Chromosomal instability at molecular level: SEQUENCE INTEGRITY
Effect:
- BASEPAIR SUBSTITUTIONS
- DELETIONS & INSERTIONS
- METHYLATIONS
6
Chromosome Instability Causes: DEFECT IN CELL DIVISION
Effects:
- Polyploidy
- Aneuploidy
7
Chromosome Instability Causes: RECOMBINATION
Effect:
- Loss of heterozygosity
8
Chromosome Instability Causes: DNA Replication
Effects:
- Amplification
- Deletions & Insertions
- Basepair Substitutions
9
Chromosome Instability Causes: DNA Repair
Effects:
- Translocations
- Fusions
10
Chromosome Instability Causes: Dysregulation of Expression
Effect:
- Methylation
11
Chromosome Instability Causes: Attrition with Cell Proliferation
Effect:
- Telomere length
12
Chromosome Instability Causes
- Defects in cell division
- Recombination
- DNA replication
- DNA repair
- Attrition with cell proliferation
- Dysregulation of expression
13
Environmental DNA Damage
1) UV
2) X-rays
3) Heat generated hydrocarbons
4) Food additives
5) Job related exposures
6) Chemotherapeutic agents
14
*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
16
*Repair mechanisms for spontaneous DNA damage:
1) Base excision repair (&single-strand break repair)
2) Methyl transferase
17
DNA repair: Why?
- Repository of hereditary information
- Blueprint for operation of individual cells
- Only biomolecule that is repaired rather than replaced
18
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"
19
Consequences of not repairing DNA damage (cell)
- Errors in division
- Chromosomal aberrations
- Apoptosis
- Senescence
- Mutations
20
Consequences of not repairing DNA damage (organism)
- Xeroderma pigmentosum
- Cockayne syndrome
- Trichothiodystrophy
21
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
22
*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
23
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?
24
Xeroderma Pigmentosum
- Affected genome maintenance system: Nucleotide excision repair (NER)
- Genome Instability: Point mutations
- Phenotype: UV-induced skin cancer
25
Cockayne Syndrome
- Affected genome maintenance system: Transition-coupled Nucleotide excision repair (NER)
- Genome Instability: Apoptosis
- Phenotype: Premature Aging
26
Trichothiodystrophy
- Affected genome maintenance system: Transition-coupled Nucleotide excision repair (NER)
- Genome Instability: Apoptosis
- Phenotype: Premature Aging
27
Ataxia Telanglectasia
- Affected genome maintenance system: DSB-R and checkpoint
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Leukemias and lymphomas
28
AT-like disorder
- Affected genome maintenance system: DSB-R
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Ataxia
29
Nijmegen breakage syndrome
- Affected genome maintenance system: DSB-R and checkpoint
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Lymphomas
30
