10/17 - DNA repair defects Flashcards
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
Cockayne Syndrome
- Affected genome maintenance system: Transition-coupled Nucleotide excision repair (NER)
- Genome Instability: Apoptosis
- Phenotype: Premature Aging
Trichothiodystrophy
- Affected genome maintenance system: Transition-coupled Nucleotide excision repair (NER)
- Genome Instability: Apoptosis
- Phenotype: Premature Aging
Ataxia Telanglectasia
- Affected genome maintenance system: DSB-R and checkpoint
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Leukemias and lymphomas
AT-like disorder
- Affected genome maintenance system: DSB-R
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Ataxia
Nijmegen breakage syndrome
- Affected genome maintenance system: DSB-R and checkpoint
- Genome Instability: Aberrations of 7 + 14 RRDS
- Phenotype: Lymphomas
Werner’s syndrome
- Affected genome maintenance system: Telomere maintenance DSB-R
- Genome Instability: Deletions, translocations, and fusions
- Phenotype: Nonepithelial tumors
Bloom Syndrome
- Affected genome maintenance system: DSB-R (replication repair) and ICL-R
- Genome Instability: Spontaneous SCEs
- Phenotype: Epithelial tumors and leukemia
Rothmund-Thompson Syndrome
- Affected genome maintenance system: TCR
- Genome Instability: Clonal translocations
- Phenotype: Osteosarcoma and skin cancer
Fanconi Anemia
- Affected genome maintenance system: ICL-R
- Genome Instability: Crosslink-induced radials and breaks
- Phenotype: Solid tumors and leukemias
Hereditary Nonpolyposis Colorectal Carcinoma
- Affected genome maintenance system: MMR
- Genome Instability: bp substitutions micro satellite instability
- Phenotype: Colon cancer
Mismatch repair in E. coli
1) Mismatches introduced during replication
2) MutS recognizes the mismatch
3) MutL stabilizes the DNA:protein complex
4) MutH discriminates between strands
5) MutH nicks near the new strand
6) UvrD unwinds the DNA from the nick
7) Exonuclease removes new strand
8) Pol3 replaces the patch
9) Ligase restores the backbone
Microsatellite Instability
- All eukaryotes contain tracts of DNA in which a single base or a small group of bases are tandemly repeated
- Expansions of these tracts are associated with a number of human diseases
- 1-3 base repeats particularly unstable in HNPCC
- Instability in some sporadic CRC tumor cells
MSI results form what
- From slippage of the polymerase during DNA synthesis
