Genomic instability and cancers Flashcards
What is genomic instability?
Genomic instability is defined as a process prone to genomic changes or an increased propensity for genomic alterations
• Genomic instability is associated with the failure of parental cells to accurately duplicate the genome and precisely distribute the genomic materials among daughter cells during cell divisions
What is a direct repair?
reversal of an alkylated base to a normal base without any intervening steps. Problem with one of the base becomes alkylated and then removed it.
What is the
The base excision repair (BER) pathway?
Removes simple alkyl and oxidative base lesions. Base is wrong and then replaced with a correct one.
What is
Nucleotide excision repair (NER)?
removes bulky, helix-distorting lesions
What is the mismatch repair?
pathway mediates the removal of mismatched bases, as well as mispairs that are caused by base alkylation lesions.
What is Homologous recombination (HDR)?
a mechanism in cells to repair double strand DNA lesions and can only be used by the cells when there is a homologue piece of DNA present in the nucleus, mostly in G2 and S phase of the cell cycle. When the homologue DNA piece is absent, nonhomologous end joining (NHEJ) is used by cells. This is less error prone than Non-homologous end joining.
Homologues pair of DNA that can be used as a template for DNA repair.
What is Non-homologous end joining (NHEJ)?
a pathway that repairs double-strand breaks in DNA. The break ends are directly ligated without the need for a homologous template
Just join the two strands together but with no template
What do PARP inhibitors do?
PARP inhibitors block the repair of single strand breaks (SSBs), which if left unrepaired are converted to double-strand breaks (DSBs) during replication.
Information about BRCA
- In normal cells of BRCA1 and BRCA2 mutation carriers (BRCA1/2+/−), these DSB lesions are repaired by homologous recombination because one copy of BRCA1 or BRCA2 is sufficient for repair proficiency, and the cells remain viable.
- However, in cells with defective homologous recombination, such as tumor cells in BRCA mutation carriers that also lost the wild-type copy of BRCA - loss of heterozygosity (LOH), double-strand breaks cannot be efficiently repaired, leading to cancer cell death and elimination of the tumor.
In a normal cell, if you have one copy that is normal and one abnormal, if you have PARP inhibitor they go to double repair but cell can still repair.
If you have inherited pair of BRCA – even though you have PARP inhibitor, cell can survive.
In tumour, also have BRCA mutation, some of the tumours if they have a copy of the gene that is normal, if you give PARP inhibitor, tumour can still survive as it can repair –> resistant tumour cell.
Some tumours can have loss of heterozygosity
which means that the tumour requires mutation, so they lose the wild type copy – both copies not working (BRCA 1 and 2) then have no functioning BRCA genes. Then causes synthetic lethality as sensitive to PARP inhibitor. Therefore, cell dies as cannot repair. This applies to both tumour and normal cells.
Describe DNA replication in dependent production of erroneous proteins?
a) Normally transcription in the nucleus produces error-free mRNAs that are translated by ribosomes to normal proteins (blue ovals) in the cytoplasm
b) In some cases, lapses in RNA polymerase (RNAP) fidelity can generate aberrant transcripts (yellow circle) that are translated into erroneous proteins (yellow oval).
c) When exposed to a genotoxic agent, RNA molecules in a cell may contain various lesions (triangles) that could induce the production of erroneous proteins during translation
d) RNA Polymerase (RNAP) can bypass numerous unrepaired damaged deoxyribonucleotides on the transcribed strand of a gene (red triangle) that can result in misincorporation events in the transcript sequence (red circles) as long as the DNA damage is not removed by one of the DNA repair pathways.
e) Transcriptional mutagenesis results in the production of a mostly homogenous mutant transcript population, which in turn leads to the production of high levels of erroneous proteins that possess the same mutant sequence, and that could alter the phenotype of the cell.
How does colon cancer develop?
Colon cancer can develop of many years. Normally, get a normal cell that first lose tumour suppressor gene APC. Therefore, the normal cells develop an adenoma (benign tumour) and the activation of RAS oncogene and then becomes a larger adenoma. Loss of tumour suppressor gene p53 AND THEN turns into a tumour. Happens over many years.
In what stage of cancer can you prevent from growing further?
PRE- cancerous
What is a Synonymous mutation?
(silent substitution) is the substitution of one base for another in an exon of a gene coding for a protein, which does not result in a change the produced amino acid sequence
What is a Nonsynonymous substitution?
is a nucleotide mutation that alters the
amino acid sequence of a protein
What cancers are associated with over-expression of EGFR?
Over-expression of EGFR is linked with many cancers including squamous cell carcinoma of head and neck, lung, cervix, vulva etc.
