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17 Cards in this Set
- Front
- Back
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Direct Repair: MGMT |
Damage from akylating agent
Agents produce 0⁶-methylguanine
Repaired by MGMT
Cysteine group on enzyme binds to methyl group on DNA and removes it.
Suicide enzyme because MGMT is permanently deactivated after doing this. - must be degraded and resynthesized |
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Direct Repair: DNA Photolyase |
Repairs dimerization of pyrimidines caused by exposure to UV light
Enzyme binds to photodimer
Breaks the bond using visible light (300-600 nm)
Restores the initial base pairs |
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Base Excision Repair: Short Patch |
Used to repair 1 damaged base ONLY
DNA glycosylase identifies and removes damaged base, results in abasic region
AP endonuclease cleaves the abasic site at the 5' end
AP lyase then cleaves the abasic site at the 3' end and removes the abasic nucleotide DNA Pol β then synthesizes missing section of strand
DNA ligase seals the nick in the backbone at the |
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Base Excision Repair: Long Patch |
Used to repair 2-10 damaged bases in a row
DNA glycosylases identify and remove damaged bases, results in abasic regions
AP endonuclease cleaves the abasic site at the 5' end
DNA Pol δ and DNA Pol ε synthesize missing segment of damaged strand using complimentary strand as template.
Abasic portion of the original stand is displaced and forms a flap because it is still attached at the 3' end
Flap Endonuclease 1 (FEN-1) removes flap DNA
DNA ligase seal the nick in the new backbone |
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Nucleotide Excision Repair: Global |
Removes a large area of one strand around damaged area of that strand and re-synthesizes
Example: T-T dimer removal and repair
XPE identifes T-T dimer
XPC binds to damaged DNA distorting its structure
XPB & XPD are helicases; they attach and unwind and unzip DNA around damaged area
XPA, XPG, & RPA (replication protein A) recognize damaged area, bind and assist in replication complex assembly
XPF & ERCC1 (excision repair cross-complimenting group 1) are endonucleases and cleave the damaged strand 5' and 3' of the damaged section - forms a 30 bp oligonucleotide
DNA Pol δ and ε along with PCNA synthesize new segment of excised strand using complimentary strand as template
DNA ligase 1 seals the nick in the backbone
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Nucleotide Excision Repair: Transcription Coupled |
RNA pol stalls when it senses damage
CSA and CSB recruit TFIIH
TFIIH "kick out" RNA pol, CSA, CSB
Nucleotide excision repair continues from there following same pathway as outline in previous card starting with XPB and XPD |
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Mismatch Repair |
Incorrect base pairing (both bases are normal)
MSH and MLH recognize mismatch and identify correct strand by looking at methylation - old (correct) strand will be methylated already; new strand will not
PCNA interacts with stalled mismatch repair complex
Helicase unwinds DNA and mismatch is repaired |
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Homologous Recombination |
Used to correct single and double stranded breaks in DNA caused by ionizing radiation / chemotherapeutic agents
Homologous end joining occurs when enzyme simply ligates the double stranded break points
Crossing over with homologous DNA segment can lead to formation of holiday junctions and synthesis of recombinant or non-recombinant repaired strands |
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Non-Homologous End Joining |
Area surrounding DNA double stranded break point is digested by endo/exonucleases for a certain distance
Double strands are then ligated together resulting in loss of DNA in the area surround the DS break |
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Complementation Groups |
Cells from two patients who were unable to repair their DNA are fused
Heterokaryons (cells with one nucleus from each patient) are examined
If the cells are still unable to repair the DNA, then you know that they posses a defect in the same repair enzyme
If the cells are able to repair DNA then the defect in one is complimented by a working gene product from the other |
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Xeroderma Pigmentosum |
Autosomal recessive
Exhibits genetic heterogeneity (9 genes involved)
Defects occur in nucleotide excision repair pathway
Clinical features include... - marked freckling of the face in children under the age of 2 - severe sunburn w/ blistering even w/ minimal sun exposure - neurological and opthalmologic problems - skin cancer is 1000x more likely
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Cockayne Syndrome |
Autosomal recessive
Genes: ERCC6 (75% of cases) & ERCC8 (25%)
Clinical features include... - short stature and premature aging - failure to thrive - microcephaly - impaired development of nervous system - photosensitivity
Other potential problems... - hearing loss - eye problems - severe tooth decay |
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Ataxia-telangietasia |
Progressive, and degenerative
Clinical features include... - Children appear normal at birth - symptoms first present around age 2 - being with wobbling / balance problems - slurred speech caused by ataxia
Ataxia: - onset means beginning of deterioration of cerebellum - progressive loss of muscle control that eventually renders patient wheel-chair bound - leads to loss of speech functions and inability to read due to loss of eye control
telangietasia: - appear shortly after ataxia onset - red spiderweb veins appear in the corners of the eyes |
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Ataxia-telangietasia [Mechanism] |
ATM encodes a protein kinase
ATM also cellular response to double stranded DNA breaks including affecting progression through the cell cycle
Without proper ATM functioning, the cell does now follow steps to minimize damage from ds breaks in DNA |
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Fanconi Anemia |
Characterized by range of physical abnormalities - early bone marrow failure - myelodysplasia - acute myelogenous leukemia
These present in 65-75% of patients w/ FA - short stature - skin pigmentation abnormalities - malformations of the thumbs, forearms, skeletal system, plus others - hearing loss - hypogonadism |
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Fanconi Anemia [Mechanism] |
Defects in recombination repair
>5 FA proteins assemble in nuclear complex
In response to DNA damage, FA complex monoubiquitinates FANCD2 which interacts with BRCA2 to initiate DNA repair.
If any of the FA proteins are not properly formed, DNA repair is much less effective |
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Hereditary Breast and Ovarian Cancer Syndrome |
BRCA1 and BRCA 2 genes
Code for nuclear proteins within the same multi-protein complex
Proteins participate in cellular response to double stranded DNA breaks
Function as tumor suppressors |
