Diseases of Defective DNA Repair Flashcards
How do mutations occur via DNA replication?
Anything prevent DNA or RNA polymerases from adding the correct new nucleotides
2 types of silent mutations
1) Mutation in DNA that has no function (junk DNA…no protein)
2) Mutation that does not alter the function of the sequence
DNA Replication errors
Can cause mutations by adding wrong nucleotide
Deaminating agents act on ______ and what is example
C,A,G
Nitrous acid (from nitrates or nitrites like bacon)
Base analogs can
Be incorporated into DNA
Alkylating agents and example
Add alkyl groups to base to block correct pairing
Mustard gas
Intercalating agents and examples
Ethidium bromide
Benzopyrene in cigarette smoke
Slide between stacked bases and distort double helix to cause errors
Types of radiation damage
DNA strand breakage (large deletions)
Dimerization of adjacent thymine bases (inhibits DNA replication)
Deamination problem
Changes one base into another and pairs with wrong base
What happens to beznopyrene in cells
Altered by CYP1A1 (hydroxylated)…added to DNA to create benzopyrene-DNA adduct
3 DNA repair mechanisms
Direct repair
Excision repair
Mismatch repair
Direct repair
Repairs thymine dimers and alkylated bases…repair proteins scan and look for lesions…once it is found, repairs without cleaving DNA or removing the base
Excision repair
Repairs thymine dimers and deaminated bases
1) Proteins recognize damage and endonuclease cuts backbone on both sides
2) Exonuclease removes damaged DNA segment
3) A DNA polymerase fills in gap and ligase seals the nick
Mismatch repair
Different because it is looking for regular bases that are paired incorrectly
1) As soon as rep fork passes sequence, mismatch repair enzymes scan newly synthesized DNA and replace
2) Enzymes use parental strand as template for DNA syntehsis repair
Example of DNA repair
Alkyltransferase reaction removes methyl groups from DNA bases
Example of excision repair
Repair of damange resulting from deamination of cytosine by uracil N-glycosylase (UNG)
UNG mechanism
Recognizes U/G mispairs and hydrolyzes N-glycosydic bond of deaminated cytosine
AP site recognized by second repair enzyme that removes the deoxyribose by cleaving the sugar-phosphate backbone on both sides of lesion
Gap filled by DNA polymerase/ligase
How does mismatch repair ID the parental strand?
More methylated (by Dam methylase)
E. coli key mismatch repair proteins
MutS, MutL, MutH
Difference between cytosine and 5-methylcytosine methylation
More efficient at turing cytosine into uracil than 5-methyl cytosine into thymidine…means amination of some can be more harmful than others
Xeroderma pigmentosum symptoms and cause
Extensive freckling
Photosensitivyt
Cataracts
Frequent skin tumors
Mutation in Excision-Repair genes
XP patients expereicne what earlier than most
Skin cancers
HNPCC caused by
Mutations in mismatch repair proteins MLH1 and MSH2…allows for microsatellite instability
Strand slippage is more likely in ______
Sequences of short nucleotide repeats
Fanconi anemia caused by
Expsosure to corss-linkeing agents (chromosomes fuse)
Fanconi anemia symptoms
Growht retardation and abnormal developmetn….stem cell failure…1000 fold risk of cancer
Why is there such a big difference in penetrance/severity of symptoms?
Proteins work in complex (eg Fanconi Anemia complex)…each protein not equally important
Xeroderma pigmentosum and Cockayne syndrome both involve
Different patients with different mutations
Interventions for paitents with DNA repair dzs
Reduce exposure to mutagens
Gene therapy to deliver normal copies
Example of gene therapy
Tx of SCID (severe combined immunodeficiency)
