Chapter 5 Flashcards
What is a proto-oncogene?
An oncogene prior to being mutated or activated. Some are present in all human cells, many are similar to transforming oncogenes present in RNA retroviruses.
Of oncogenes and TSG, one class of gene is NOT seen to be mutated in germlines. Which CAN be mutated in germlines and give a classic example of this scenario.
Oncogenes NOT mutated in germline bc this would be embryonic lethal.
Germline TSG mutations are possible (ex: retinoblastoma, p53 - Li-Fraumeni)
The processes of transcription and translation are the making of what from what?
Transcription: DNA to RNA
Translation: RNA to protein
In addition to mutations such as deletions and translocations, there are other causes of genetic instability including gene amplification and epigenetic changes.
Explain gene amplification and the changes seen in cells w/ these abnormalities.
Give 1 example of gene amplification that we deal w/ as oncologists on a regular basis.
Gene Amplification: results in constitutively enhanced level of gene expression. Ex: MDR overexpression.
Amplification is noted in the cells via double minute chromosomes (extrachromosomal chromatin) or homogenously staining regions (present w/in the chromosome)
Name and describe the types of epigenetic changes
Epigentic Changes:
Changes outside or not directly affecting DNA.
METHYLATION: Methyl (-CH3) group is #1 mc epigenetic change in people. Occurs in half human tumors. Methyl groups accumulate in normally unmethylated CpG islands within DNA. This silences transcription by blocking areas for the DNA polymerase to bind. Usually effects TSG, apoptosis genes, DNA repair genes, and other genes you would have inactivated when there is genetic instability and cancer.
ACETYLATION:
affects how chromatin is coiled around histones and t/f gene expression. DEACYTYLATION associated w/ silencing of genes whereas ACETYLATED genes are generally expressed.
UBIQUITINATION: clearing of protein after translation
Why are epigenetic changes attractive as potential cancer treatment targets?
Methylation and acetylation are reversible so can act as target for treatment.
EX: Retinoic acid can reverse DNA methylation and lead to reactivation of regulatory genes
What effect does an HDACi have on gene expression?
HDACi promote acetylation which leads to uncoiling of DNA from the histones and increased gene expression of TSG = ANTI-CANCER EFFECT
Many DNA repair deficits are lethal mutations if inherited. However some well recognized conditions exist such as XP and AT. What are these disorders?
XP (xeroderma pigmentosum):
Defect in NER. Occurs dt point mutation and results in predisposition to UV induced skin cancer.
AT (ataxia telangiectasia):
Defect in DNA double strand break repair. Defective protein is ATM (ataxia telangiectasia mutated) which results in chromosome aberrations and lymphoma.
Transcription Coupled Repair
How does it work. Is it error free or prone?
Certain DNA lesions result in inability to transcribe RNA from DNA, which if occurs long enough will lead to cell death. In general, DNA polymerases are very accurate. However, in TCR, other error prone DNA polymerases are used to bypass the stalled location. Because of error prone nature, malignant transformation can occur.
Direct reversal of repair
How does it work. Is it error free or prone?
Direct repair of O6 Methylguanine:
N nitrosourea compounds (CCNU) can react w/ DNA to form O6 methylguanine which can form a G:C to A:T mutation by anomalous base pairing during replication.
Enzyme in cells (O6 alkylguanine DNA alkyltransferase) can help prevent malignant transformation by removing the O6meG adduct before the base mutation occurs.
If expression is low dt methylation at CpG islands (promoter) the enzyme is not expressed and repair does not occur so mutations are high.
If expression is too high it can lead to chemo resistance against temozolomide and BCNU, etc.
Error prone/accurate doesn’t apply, rather expression levels are nb for this type of repair.
Mismatch Repair (How does it work. Is it error free or prone?)
recognizes and restores mismatched nucleotides that arose during DNA replication or w/in DNA insertion or deletion loops. Multiple MMR proteins join together in complexes to recognize specific mismatches. These are 1 example of a TSG bc if mutated, pt will be more cancer prone. Commonly mutated in colon cancer in ppl.
Base Excision Repair
How does it work. Is it error free or prone?
(used for repair of oxidative dmg and ionizing RT)
Involves enzymatic removal of damaged DNA base and replacement w/ a new base (sometimes a length of bases 2-13 in a row can also be repaired by this method)
Nucleotide Excision Repair
How does it work. Is it error free or prone?
NB for UV DAMAGE REPAIR
24-32 bases are excised on both sides of the lesion
DNA polymerase uses the opposite strand to repair the defect w/ the appropriate non-damaged bases
Homologous Recombination (How does it work. Is it error free or prone?)
DNA ds break repair
In cells, abnormal dsDNA breaks occur from exogenous agents such as ionizing RT or certain chemo.
Normal dsDNA breaks are generated during recombination bt homologous chromosomes during meiosis or for VDJ rearrangements…
HR is predominantly seen in germline cells and during S and G2 phases.
ERROR FREE. Extensive homology required bt the region of the dsDNA break and the sister chromatid that is being used as the template
Non-homologous End Joining
How does it work. Is it error free or prone?
More common than HR. Does not require as much homology, and simply links ends of DNA together which can easily result in loss of a number of bases.
Used in somatic cells and in G1
Also for dsDNA break repair
ERROR PRONE
