Definitions
This DNA repair process rectifies base-base mismatches and insertion/deletion errors.
What is DNA Mismatch Repair?
This group of four proteins recognizes mismatched base pairs and small insertion/deletion errors.
MSH2, MSH6, MLH1, PMS2
1. The MMR complex consists of MutSa (MSH2, MSH6) and MutLa (MLH1, PMS2), which recognize newly-synthesized DNA sequences with mismatched base pairs or small insertions/deletions
2. Exonuclease 1 excises portion with replication error
3. DNA polymerase d inserts missing nucleotides
4. DNA Ligase 1 ligates nick
Cisplatin-induced intrastrand crosslinks between Guanine bases are rectified by this DNA repair process.
What is Nucleotide Excision Repair (NER)?
Cisplatin-DNA adducts cause gross distortion of the DNA helix. These lesions are primarily repaired through NER.
This DNA repair process rectifies lesions that result in gross distortions to the DNA double helix
What is Nucleotide Excision Repair?
Gross DNA distortions (caused by UV radiation, platinum drugs, tobacco smoke, etc.) are detected and incised, and unwound by this protein complex.
What is the TFIIH complex?
1. Lesion is recognized by TFIIH complex
2. TFIIH endonucleases cut both strands, helicases unwind strands
3. DNA polymerase and ligase re-synthesize the strand using template and ligate
Humans who are homozygous for inactivating mutations in the NER pathway are characterized by early onset of this cancer.
What is skin cancer?
Ultraviolet radiation causes covalent linkages between adjacent pyrimidines, resulting in gross distortions in the DNA helix. Patients NER defects cannot resolve these lesions and thus become extremely sensitive to UV radiation-related skin damage.
This DNA repair process rectifies lesions that do not substantially distort the DNA helix
What is Base Excision Repair (BER)?
Small base lesions include:
- Deamination
- Oxidation
- Alkylation
- Spontaneous base loss
This protein creates an abasic site in the first step of this DNA repair process.
What is DNA glycosylase?
1. DNA glycosylase removes the damaged base
2. AP endonuclease excises 5' to the deoxyribose in the AP site, and DNA polymerase b lyase removes the deoxyribose
3. DNA polymerase b inserts the missing nucleotide
4. DNA Ligase III ligates the nick
This syndrome, resulting from inherited mutations in MSH2, MSH6, MLH1, or PMS2, predisposes patients to an elevated risk for colon, endometrium, ovary, stomach, and biliary tract cancers.
What is Lynch Syndrome?
1. The MMR complex consists of MutSa (MSH2, MSH6) and MutLa (MLH1, PMS2), which recognize newly-synthesized DNA sequences with mismatched base pairs or small insertions/deletions
2. Exonuclease 1 excises portion with replication error
3. DNA polymerase d inserts missing nucleotides
4. DNA Ligase 1 ligates nick
These are the four forms of DNA damage that can be corrected by base excision repair.
Deamination (cytosine to uracil, adenine to hypoxanthine)
Oxidation by reactive oxygen species
Alkylation (addition of alkyl groups to bases)
Spontaneous base loss
This highly carcinogenic polycyclic aromatic hydrocarbon (PAH) is present in cigarette smoke and is metabolized by cytochrome p-450 to produce DNA adducts.
What is Benzo[a]pyrene?
P-450 metabolizes benzo[a]pyrene to form highly reactive epoxides that predominantly react with adenine and guanine.
This glycosylase can recognizes and removes 8-oxo-guanine specifically paired to adenine.
What is MUTYH?
1. Oxidative stress can cause oxidation of guanine to 8-oxo-guanine
2. If 8-o-g lesion is not corrected by BER, it will bind to adenine instead of cytosine
3. MUTYH recognizes 8-o-g bound to adenine, and removes the adenine
4. 8-o-g returns back to the BER pathway
What is the lifetime radiation dose (in mSv) below which the risk of cancer has not been demonstrated?
What is 100 mSv?
Chest x-ray: 0.1 mSv
Whole body CT: 10 mSv
Lifetime cancer risk threshold: 100 mSv
Total cancer treatment dose: 50,000 mSv