DNA Repair Defects - Lecture 6

Question 1

Methods of DNA Repair

Answer 1

• Nucleotide excision repair - Large base changes
• Interstrand cross-link repair - ICL damage
• Base excision repair - Small base changes
• Homologous Repair, Non-homologous end joining - Double stranded breaks

DNA repair proteins are housekeeping proteins
DNA is the only biomolecule that is repaired rather than replaced

Question 2

Repair mechanisms for environmental (exogneous) DNA damage

Answer 2

1) NER
2) HR/NHEJ
3) ICLR

Defects in NER lead to cancer

Question 3

Repair mechanisms for spontaneous (endogenous) DNA damage

Answer 3

1) BER
2) Methyl transferase

Defects in BER lead to embryonic lethal conditions

Question 4

Cellular consequences of failure to repair DNA damage

Answer 4

• errors in cell division
• chromosomal aberrations
• apoptosis
• senescence

Question 5

Organismal consequences of failure to repair DNA damage

Answer 5

• Xeroderma pigmentosa
• Cockayne syndrome
• Tricothiodystrophy

Question 6

Li-Fraumeni Syndrome

Answer 6

Chromsome 17p - TP53 gene

• TP53 normally blocks replication when DNA damage occurs, recognizes when the cell is too damaged, and sends the cell into apoptosis
• Defects lead to cancer
• Constituitively active TP53 is protective against cancer but leads to premature aging due to increased apoptosis

Question 7

DNA Repair Process

Answer 7

1) Recognize damage
2) Remove damage
3) Restore coding information
4) Restore integrity of DNA backbone (DNA ligation)

Question 8

Xeroderma Pigmentosa

Answer 8

Caused by: Defects in NER
Leads to: Unstable base-pair substitutions
Causes: UV induced skin cancer

Question 9

Cockayne Syndrome

Answer 9

Caused by: Defects in transition-coupled repair
Leads to: Cell death
Causes: Premature aging

Question 10

Tricothiodystrophy

Answer 10

Caused by: Defects in transition-coupled repair
Leads to: Cell death
Causes: Premature aging

Question 11

Ataxia Telangiectasia

Answer 11

Caused by: Defects in double-stranded break repair and checkpoints
Leads to: Aberrations of 7 and 14, radio-resistant DNA synthesis
Causes: Leukemias and lymphomas, extreme radiation sensitivity, premature aging, ataxia

Question 12

AT-Like Disorder

Answer 12

Caused by: Defects in double-stranded break repair
Leads to: Aberrations of 7 and 14, radio-resistant DNA synthesis
Causes: Ataxia, NO CANCER, radiation sensitivity

Question 13

Njimengen Breakage Syndrome

Answer 13

Caused by: Defects in double-stranded break repair
Leads to: Aberrations of 7 and 14, radio-resistant DNA syntehsis
Causes: Lymphomas, radiation sensitivity, growth retardation

Question 14

Werner’s Syndrome

Answer 14

Caused by: Defects in telomere maintenance and double-stranded break repair
Leads to: Deletions, translocations, and fusions
Causes: Premature aging, radiation sensitivity, non-epithelial tumors

Question 15

Bloom Syndrome

Answer 15

Caused by: Defects in double-stranded break repair and interstrand cross-link repair
Leads to: Spontaneous sister chromatid exchange
Causes: Epithelial tumors, premature aging, leukemia
-most cancer-prone genetic disorder known to date

Question 16

Rothmund-Thompson Syndrome

Answer 16

Caused by: Defects in transcription-coupled repair
Leads to: Clonal translocations
Causes: Osteosarcoma, skin cancer, growth retardation

Question 17

Fanconi Anemia

Answer 17

Caused by: Defects in interstrand cross-link repair
Leads to: Cross-link induced radials and breaks
Causes: Solid tumors and leukemias, pancytopenia, renal and skeletal abnormalities

Question 18

Hereditary Non-Polyposis Colon Cancer

Answer 18

Caused by: Defects in mismatch repair
Leads to: Unstable base-pair substitutions and microsatellite instability (template slippage, expansion repeats)
Causes: Colon cancer