DNA mutations and repair

Question 1

Describe somatic and germine mutations

Answer 1

Somatic mutations involve somatic cells and deal with aging and cancer. Germline mutations involve gametes or their precursors and deal with genetic diseases. a) dominant mutations cause disease in heterozgous and homozygous. b) recessive mutations caused in homozygous BUT not in heterozygous. *frequency: base substitutions most common in germline mutations

Question 2

What are the 5 types of mutations and what are there frequencies.

Answer 2

1. single-base substitution (“point mutations”) a) transition- purine to purine or pyr. to pyr b) transversion- purine for pyr. or pyr. for pur. –after DNA replication. can be mutated or unchanged. 2. insertion and deletion (“indel”) 3. translocation: piece of one chromosome breaks off and attaches to another chromosome 4. duplication: too much of the gene. Most commonly occurs in crossing-over in meiosis1 “homologous recombinants” 5. Abnormal Chromosome # “SIT DAd(deletion)”

Question 3

How can mutations affect gene function?

Answer 3

1. Loss of function mutation (most common) 2. Haploininsufficiency: loss of function mutation causing problems for heterozygotes 3. Dominant negative mutation: A loss of function that disrupts the normal gene product in heterozygotes. 4. Gain of function mutation: is over-expressed, is more active than normal, does not respond to negative controls, has new properties.

Question 4

causes of mutation

Answer 4

Replication errors or induced DNA damage: 1. spontaneous tautomeric shifts 2. Ionizing radiation (X-rays, radioactivity) 3. UV radiation (sunlight) non-specific damage to DNA (ex. pyrimadine dimer) Chemical -free radical: through oxidation -base analogs -deaminating agents (usually HNO2) -alkylating agents -agents forming large adducts -intercalating agents– planar, aromatic structures that insert themselves b/w base pairs, pushing them apart. cause small insertions and deletions **Cells are most sensitive to mutagens during the S phase

Question 5

DNA repair systems

Answer 5

1. 3’- exonuclease activities: replication errors

2. post-replication mismatch repair: replication errors (associated with heredity)

3. AP endonuclease: baseless (“Apurinic”) sites

4. Base excision repair: abnormal bases

5. Nucleotide excision repair: bulky lesions. 2 types: (ex. fixing pyrimidine dimer)

• genome-wide
• transcription-coupled

6. Repair of double-strand breaks:

• Non-homologous end joining—region with altered segment due to missing nucleotides. Contained mutated region in G1
• homologous end-joining (homologous recombination): complete sequence restored by copying from second chromosome. Occurs after S phase

Question 6

Provide an example of a mutational hot spot

Answer 6

5-methyl-cytosine is a mutational hot spot. This mutation is typically not repaired b/c it creates a normal pyrimidine (thymine) when deaminated.

Question 7

What two diseases are assosciated with defects to nucleotide excision repair

Answer 7

1. Xeroderma pigmentosum:
   - Defect of genome-wide nucleotide excision repair-cannot repair pyrimidine dimers. Associated with sunburn, and skin cancer. Autosomal recessive. 7 different types
2. Cockayne syndrome:
   - Defect of t**ranscription-coupled nucleotide excision repair. **
   - poor growth, neurological problems, early senility, autosomal recessive. 2 different types

Question 8

What is Lynch sydrome and what DNA repair defect is it associated with?

Answer 8

Lynch syndrome (hereditary non-polyposis colon cancer) is a autosomal dominant inheritance disease. This syndrome is caused by a defect of post-replication mismatch repair. People effected with Lynch sydrome have a greater than 50% risk of colon cancer and also have an increased risk of other cancers.

Why does this cause cancer? All cells have a heterozygous defect in mismatch repair protein. When a somatic mutation disrupts the single intact copy of a gene, the cell becomes a mutator, and some of these mutator cells become cancer.

Question 9

Describe ataxia-telangiectasia and what causes it?

Answer 9

Ataxia-telangiectasia is caused by mutations in the ATM protein kinase, a signaling protein required for the repair of DNA double-strand breaks. Abnormalities include cerebellar ataxia starting in early childhood, thymus hypoplasia, immunodeficiency, lymphoreticular malignancies, dilation of small blood vessels (telangiectsia), and extreme sensitivity to ionizing radiation.