10/17 - DNA repair defects Flashcards Preview

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Flashcards in 10/17 - DNA repair defects Deck (37)
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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

Werner's syndrome

- Affected genome maintenance system: Telomere maintenance DSB-R
- Genome Instability: Deletions, translocations, and fusions
- Phenotype: Nonepithelial tumors