Functions And Dysfunctions (2) Flashcards
CGH Arrays
Comparative Genome Hybridization: what to use to detect variations in copy number (CNVs)
-people usually have 1000 differences (CNVs) which are the basis for our differences and for disease states
Long Terminal Repeats
LTRs
- identical sequences of DNA (repeat hundreds or thousands of times)
- found at either end of retrotransposons (proviral DNA)
- formed by reverse txn of retroviral RNA
- used by viruses to insert genetic material into host genome
Alternative RNA splicing
approximately two alternative splice products per gene (average)
- 99% of all introns begin with […GT] and end with [AG..]
- 26,000 genes encode around 100,000 proteins
- 15% of all mutations affect RNA splicign
- numerous functional motifs/domains appear in various proteins throughout proteome
Methylation
-methyl group added to DNA molecule (cytosine and adenine) by methyl transferase enzymes
-changes the activity of a DNA segment, without chaining sequence
-represses gene transcription when at gene promoter
-essential for normal development
associated with a number of key processes: genomic imprinting, x-chromosome inactivation, repression of transposable elements, aging carcinogenesis
Polymerase Proofreading
- Most errors are corrected by proofreading
- enzyme: DNA polymerase
Direct Repair
- can break bonds formed by UV light and can transfer methyl group from G to C to reverse the damage
- damage: pyrimidines dimers, methyl G
- Enzyme: DNA photolyase, methylguanine, methyltransferase
Base Excision Repair
- Enzyme mediated flipping out of base from helix
- Damage: single base mismatches, depurinations
- Enzymes: DNA glycosylase, DNA polymerase has this function as well
Nucleotide Excision Repair
- multi-enzyme complex scans DNA for distortion in double helix instead of a specific base change. It cleaves phosphodiester backbone on both sides.
- Damage: pyrimidines dimers, BPDE-guanine adducts
- Enzyme: NER protein complex, DNA polymerase, DNA ligand,
- Disease: Xeroderma Pigmentosum (and Cockayne syndrome)
Mismatch Repair
- repairs mismatch from DNA-dependent DNA polymerase
- damage: mismatch base in daughter strand
- Enzymes: MER complex (uses MutS and MutL)
- Disease: heredity nonpolyposis colorectal cancer
Recombination
- non-homologous ends joining brings broken ends together and rejoins Gs by DNA ligation (one or more nucleotides will be lost)
- Damage: double stranded breaks (causes by ionization radiation, replication errors, oxidizing agents); cross-linking
- Enzymes: multiple proteins including DNA ligand
- Disease: Brac1/2 breast cancer
Transcription Coupled Repair
- works with BER, NER, and others to repair genes that are being expressed when he damage occurs
- Damage: stalled RNA polymerase during txn only (directs machinery there)
- Disease: Cockayne Syndromes
Hereditary nonpolyposis colorectal cancer
individuals with inherited mutations in one of the alleles of the MER complex genes have an increased susceptibility to hereditary nonpolyposis colorectal cancer. A mutation in the other allele would render the MER complex nonfunctional and lead to tumor development
Xeroderma pigmentosum
NER defect. Skin of these people is extremely sensitive to direct sunlight and they are prone to developing melanomas and squamous cell carcinomas. The UV component of sunlight causes thymine dimers to form in the DNA. People with this defect cannot repair these like normal individuals can.
Cockayne Syndrome
AR, congenital disorder. Mutant genes involved in TCR of DNA. If DNA is not repaired, then cell dysfunction and cell death may occur.
- RNA polymerase permanentely stalled at site of damage in imp’t genes
- Characterized by developmental and neurological delays, photosensitvity, and progeria (premature aging). Death occurs within first 2 decades of life
BRCA mutation and breast cancer
BRCA 1 and 2 are tumor suppressor genes. Mutations cause a 5x increase in risk for breast cancer and/or ovarian cancer. Men can also increase risk for breast cancer. Recombination defect.
