DNA Repair: damage and mutation Flashcards
Short term consequences of DNA damage
Reduced proliferation
altered gene expression
cell death
Long term consequences of DNA damage
Aging
diseases especially cancer
Errors of Replication
wrong base is incorporated by DNA polymerase
only occurs during S phase of cell division
Spontaneous Lesions
Chemical changes that occur spontaneously
Exposure to mutagens: sunlight, radioactivity, ionizing radiation
occurs in resting cell
Tautomerism
ability of certain chemicals to exist as a mixture of two interconvertible isomers
Blooms syndrome
Defect in gene encoding DNA helicase enzyme
causes torsional strain upstream and chromosomal inability
Autosomal recessive
Characteristics of Blooms Syndrome
Smaller than average
narrow chin, prominent nose and ears
Facial rash upon exposure to sun
often get diabetes and have neurological, lung and immune system deficiencies
Depurination
Breaking of glycosidic bond between base and sugar in purine nucleotides
Sugar phosphate backbone remains but base is lost
Formation of apurinic sites
Deamination
Loss of amine group from a base
ex)Cytosine deaminates to form uracil
Oxidative damage
Result of the production of reactive oxidative compounds due to oxidative metabolism
Causes oxidative damage to many parts of the cell including addition of oxygen groups to nucleotide bases
UV radiation
Generates several deleterious photoproducts
cyclobutane, pyrimidine dimers, 6-4 photoproducts
covalent linkages between adjacent pyrimidine bases on the same strand
The dimers will interfere with normal base pairing and block replication
Nucleotide excision
Removes more than a few bases around a damaged site
How pyrimidine dimers formed by UV damage are repaired
Excision repair
Recognition of damage
Recruit endonucleases
Region excised
DNA Polymerase fills in gap
Ligase seal nick
Xeroderma Pigmentosa
Autosomal recessive
Locus heterogeneity- many genes involved in the pathway
Clinical sun sensitivity
DNA Damage is cumulative and irreversible
what is an example of a reason why some regions would be considered a mutation hotspot?
deamination
ex) 5 methyl cytosine deaminating to form thymine
- creates T-G base pairing instead of C-G
- The repair machinery has to guess whether to correct the mistake back to C or leave the T base pair in DNA
BRCA1 & 2 (autosomal dominant)
Process affected: repair by homologous recombination
Women with the mutation for either gene have an 85% risk of developing breast cancer by age 70
risk of developing ovarian cancer
Ataxia Telangiectasia
Defects in ATM gene(11q22-23)
Autosomal recessive inheritance pattern
increased cancer risk
Affects cerebellum and immune system
Ocular telangiectasia common
ATM gene(11q22-23)
Serine-threonine protein kinase responsible for detecting DNA damage and activating cell cycle arrest and DNA repair proteins(like p53)
UV Light
Generation of deleterious photoproducts
-pyrimidine dimers or thymine dimers
The dimers will interfere with normal base pairing and block replication
Hereditary nonpolyposis colon cancer
Autosomal dominant
resulted from mutations in genes encoding mismatch repair proteins MSH2, MLH1,PMS1, PMS2, MSH6
Results in micro satellite instability
