DNA Mutations And Repair Mech

Question 1

Mutation

Answer 1

Change in genomic sequence

• generally used for disease-causing variants
  1. Point- single base change
  2. Silent- specifies same aa
  3. Missense- specifies different aa (50%)
  4. Nonsense- premature stop (10%)
  5. Insertion/deletion- add/remove one or more bases
  6. Frameshift (25%)
  7. Rearrangements
  8. RNA processing (10-20%)

Question 2

Polymorphism

Answer 2

Rare genetic variant- allele occurs in 1%< of a population

• independent of functional or pathogenic relevance of alteration
• can be beneficial or harmful
  1. Single nucleotide polymorphisms (SNPs)- I bp changed at a specific genome location (affects 2 alleles)
  2. Insertion/deletion (indels)- 1-100 bp added/removed

Question 3

Point mutations

Answer 3

1. Base substitution
   * transition: AG or CT
   * transversion: pyrimidine purine
2. Base addition/deletion

Question 4

Molecular consequence of mutation

Answer 4

1. Gain-of-fxn: one allele produces novel or xs protein
   * can be harmful, neutral, or beneficial
2. Loss-of-fxn: one allele doesn’t produce protein
   * disease (usually)
   * depends on autosomal dominant/recessive
3. Dominant (-) mutation: one allele produces abnormal protein that cancels out normal one made by other allele

Question 5

Trinucleotide repeat expansion

Answer 5

1. Huntington’s disease
2. Fragile X syndrome
3. Myotonic dystrophy (type 1)

Question 6

Huntington’s disease

Answer 6

Repeat CAG (gln) in coding region

• need 36< repeats to see disease
• xs gln
• aggregated Huntington’s protein -> precipitated

Question 7

Fragile X syndrome

Answer 7

(CGG) > 200 in UTR

*doesn’t directly affect proteins

Question 8

Myotonic dystrophy (type 1)

Answer 8

(CUG) 100-1000 in UTR

Question 9

Sources of DNA damage

Answer 9

1. Endogenous: mistakes during replication, basal mutation rate, tautomeric shift
2. Exogenous (majority): ionizing radiation, hydrocarbons (cigarette smoke), ROS, chemo agents

Question 10

DNA repair

Answer 10

1. DNA proofreading
2. Mismatch repair
3. Excision repair
4. dsDNA repair

Question 11

DNA proofreading

Answer 11

DNA polymerase uses 3’->5’ exonuclease fxn during replication

Question 12

Mismatch repair

Answer 12

• several repair proteins
• recognize methylation in parent strand - cleave unmethylated spot on daughter strand
• DNA polymerase and ligase repair

Question 13

Hereditary nonpolyposis colorectal cancer (lynch syndrome)

Answer 13

Caused by mutation in any repair protein used in mismatch repair
*predisposed to other cancers

Question 14

Excision repair

Answer 14

1. Nucleotide excision- repairs T dimers
2. Base excision- one base at a time
   * starts w/ spontaneous deamination -> wrong base
   * other enzymes cleave

**both use DNA polymerase and ligase to repair

Question 15

Xeroderma pigmentosum

Answer 15

Nucleotide excision repair mutation

*skin tumors, photosensitivity, cataracts, neurological abnormalities

Question 16

Cockayne syndrome

Answer 16

Defective repair of UV damage by excision repair

• very rare
• small stature, skeletal abnormalities, optic atrophy, deafness, photosensitivity, mental retardation

Question 17

dsDNA repair

Answer 17

1. Homologous recombination- more precise mechanism
   * similar mech to recombination in meiosis
2. End joining- can lead to parts cut off