Lecture 10: Genomic Regulation Flashcards
What do Nucleoside Analog Inhibitors do and what are examples of them?
- nucleosides lacking 3’-OH act as chain terminators that inhibit replication (convert to dNTPs first)
Ex:
- Ara-C –> leukemia
- AZT –> HIV therapy
- Acyclovir
Ionizing Radiation damage types
- strand breaks, chemical base modification, DNA-protein cross-linking
Non-ionizing Radiation damage types
- sunlight
- thymine dimers, thymine 6:4 covalent linkage
Spontaneous Mutation damage types
- Depurination –> lose 5000 purines/day
- Deamination –> lose amine group
- Cytosine –> Uracil
- Adenine –> Hypoxanthine
- Guanine –> Xanthine
What are CpG islands?
- in promoter region; C-phosphate-G
- methylation coverts cytosine to thymine, causing stable silencing of genes (Cancer/DNA Repair genes)
- DNA repair relatively ineffective
Cross-linking/Intercalation and carcinogens
- Benzo[a]pyrene converted to BPDE via colon enzymes
- converting procarcinogen into a carcinogen
What are 4 common cross-linking agents?
- nitrogen mustard (mustard gas)
- cisplatin
- mitomycin C
- carmustine
What are 2 common alkylating agents?
- Dimethyl sulfate (DMS)
2. Methyl methanesulfonate (MMS)
What is a common intercalating agent?
thalidomine
MSH2/3/6, MLH1, PMS2 phenotype and defective enzyme
- colon cancer
- defective mismatch repair
Xeroderma Pigmentosum phenotype and defective enzyme
- skin cancer, UV sensitivity, neurological abnormalities
- defective excision repair
Ataxia telangiectasia phenotype and defective enzyme
- leukemia, lymphoma, genome instability
- defective ATM protein (protein kinase activated by DS breaks)
BRCA2 phenotype and defective enzyme
- breast, ovarian, prostate cancer
- defective homologous recombination
Fanconi Anemia phenotype and defective enzyme
- congenital abnormalities, leukemia, genome instability
- defective DNA interstrand cross-link repair
Base Excision Repair
- repairs: single base mismatches, nondistorting alt.
- base, then backbone removed; polymerase repairs and ligase seals nick
Nucleotide Excision Repair and diseases associated with its defect
- repair chemical adducts that distort DNA
- nicks DNA on both sides of damage site, removes DNA segment, then polymerase repairs
diseases: Xeroderma Pigmentosum
Mismatch Excision Repair and diseases associated with its defect
- MutS binds to mismatch, MutL scans for nick and removes nicked strand
disease: Hereditary nonpolyposis colorectal cancer
Double Stranded Break Repair (2 ways)
- Nonhomologous End Joining (two flat ends stuck together) –> LOSE OF NUCLEOTIDES
- Homologous End Joining (damage repaired using sister chromatid)
Transcription-Coupled Repair and diseases associated with it
- DNA repair on sequences being actively transcribed by linking RNA polymerase with DNA repair
- RNA stalls at lesions and directs DNA repair machinery there
disease: Cockaynes Syndrome
Xeroderma Pigmentosum
- skin extremely sensitive to direct sunlight, prone to developing melanomas and squamous cell carcinoma
- UV light causes thymine dimer development
- proliferates in individuals w/defective NUCLEOTIDE EXCISION REPAIR (NER)
Hereditary Nonpolyposis Colorectal Cancer
- defective in mismatch excision repair system (MER)
- loss of good copy of MER gene would allow tumor to grow
Cockayne Syndrome
- defect in TRANSCRIPTION COUPLED REPAIR
- developmental/neurologic delay, photosensitivity, premature aging
- ERCC6/ERCC8 genes are mutated (autosomal recessive)
BRCA Associated Breast Cancer
- mutations in BRCA1/2 tumor supressor genes
- defect in recombination repair system
Histone Acetylation (HATs) and Histone Deacetylation (HDACs)
- HATs - acetylate core histones to neutralize (+) charged Lysine = chromatin DECONDENSATION
- HAT inhibitors show treatment of cancer, Alzheimers, rheumatoid arthritis - HDACs - remove acetyl groups from Lysines on core histones and nonhistone proteins
- HDAC inhibitors valproic acid and vorinostate are used as anticonvulsive/anticancer drugs
Rifampicin
- inhibits Bacterial RNA synthesis (antibiotic); binds to Beta subunit of RNA polymerase
- upregulates hepatic cytochrome P-450 and increases metabolism of other drugs
- red color to urine, sweat, and tears for short time after administration
What are two common HDAC inhibitors?
vorinostat and entinostat
Methylation
- methyl group added to cytosine and adenine
- represses gene transcription when at gene promoter
- happens at CpG Islands and helps stably silence genes
Ubiquitin
- in eukaryotic cells; attaches to lysine 48/63 residues on target proteins
- Lysine 48 –> proteasome degradation
- Lysine 63 –> signaling, trafficking, endocytosis, DNA repair
