DNA repair

Question 1

Hereditary non-polyposis colon cancer (HNPCC)

Answer 1

Inherited mutation in one copy of mismatch repair gene (MMR):
Predisposition to hereditary nonpolyposis colon cancer (HNPCC)
Second copy of the gene is spontaneously mutated.
Mutations in human homologs of mutS and mutL are involved.

Question 2

breast cancer and homologous end-joining

Answer 2

Repair of double stranded breaks by homologous end-joining restores the original sequence: no loss of sequence.
Cells lacking functional BRCA1 and BRCA2 proteins show defect of double-stranded break repair by homologous recombination.
Inherited mutations in BRCA1 and BRCA2 predispose women to breast and ovarian cancer.

5% of breast cancer cases are familial.
BRCA1 and BRCA2 are breast cancer susceptibility genes.
BRCA1- chromosome 17q21: 1863 amino acids
BRCA2- chromosome 13q12: 3418 amino acids
Susceptibility to breast cancer in individuals with mutations is:
Autosomal dominant
Elevated risk for other cancers in BRCA mutation carriers.

Initial studies indicated involvement of BRCA1 in repairing DNA damage.
BRCA1 is also involved in transcriptional regulation of genes activated in response to DNA damage.
BRCA1 and BRCA2 interact with other proteins that activate repair of double strand breaks and initiate homologous recombination.
Tumor suppression.
Maintenance of genomic integrity.

Question 3

Werner syndrome

Answer 3

Werner syndrome:
Autosomal recessive
cataracts
changing of skin conditions
atypical short stature
premature graying or thinning of the hair.
Patients also often develop hypogonadism, osteoporosis, diabetes mellitus, atherosclerosis and cancers (sarcomas)

WRN protein:
Helicase of RecQ family
Helicase activity and 3’-5’ exonuclease activity
WRN protein is involved in:
Replication, cell cycle regulation, DNA repair (base excision), transcription, telomere maintenance.

Question 4

Bloom Syndrome

Answer 4

Bloom syndrome:
Autosomal recessive:
stunted growth
sunlight sensitivity
chromosome breakage 
immunologic deficiency
 infertility
increased risk for neoplasia.

Bloom (BLM) protein:
Helicase of RecQ family (helicase activity only; no 3’-5’ exonuclease activity)
Mutations in the protein lead to DNA repair deficiency