DNA, Genes & Proteins Flashcards
(41 cards)
1
Q
What is pharmacogenetics?
A
Pharmacogenetics is the study of how variations in a single gene affect an individual’s response to a specific drug.
2
Q
What is pharmacogenomics?
A
Pharmacogenomics is the study of how a person’s genetic makeup affects their response to drugs.
3
Q
Regulation of proteins - 2
A
- Kinases phosphorylate proteins to upregulate
- Phosphatase removes the kinase to downregulate
4
Q
How can proteins cause disease - 2
A
- Kinases can cause proteins to be over & under expressed.
- e.g. Constitutive activation can cause them to be constantly activated.
5
Q
What are alleles - 3
A
- Different form of gene typically leading to phenotypic change & can predispose to diseases.
- Inherited from each parent.
- Alleles are dominant or recessive
6
Q
Autosomal dominant alleles
A
Will express itself in the phenotype of a heterozygous individual if passed on.
7
Q
Autosomal Recessive Alleles - 2
A
- Both parents have to be carriers for the condition to be passed on
- Has to be homozygous to present the phenotype.
8
Q
X-Linked recessive alleles - 2
A
- Allele linked to the X chromosome
- Females must be homozygous but males can be heterozygous for the disease to manifest.
9
Q
What can single nucleotide polymorphisms lead to - 2
A
- Changes in amino acid codon
- Affect levels of protein expression
10
Q
What is a single nucleotide polymorphisms & what can they tell you - 2
A
- Single nucleotide polymorphisms: DNA sequences variation of a single nucleotide at the same position in genome between members of the same species.
- Shows genetic predisposition to diseases.
11
Q
What is a single sequence repeat (SSR) - 2
A
- A tandem repeat of 2-8 base sequences.
- Each individuals is different allowing for genetic fingerprinting
- E.g. unique genome leads to fingerprints
12
Q
SNPs’ effects on CYP450 - 2
A
- SNPs affect these the most & can cause variation in metabolism speed
- Has a variety of effects.
13
Q
Personalization of medicines - 3
A
- Individuals screened for common SNPs.
- Typically as quick swab test to develop patient specific regiments.
- Map diseases to genomes: Links mutations or polymorphisms to diseases, greater stratifying patients to optimise treatment.
14
Q
Advantages of personalized medicines - 4
A
- Less Adverse Drug Reactions
- less lack of response
- better vaccines
- overall decrease in healthcare cost.
15
Q
Define Mutation
A
A change in protein structure function that causes disease.
16
Q
Effect of mutation location - 3
A
- Can affect the outcome & significance of the disease.
- Inherited Diseases - Mutations in genes encoding for essential functional proteins
- Cancer - Mutations in genes encoding for regulation of growth & survival
17
Q
Normal control mechanisms of mutations - 4
A
- Heterozygosity - two copies of genes to minimise loss of function due to mutations
- Apoptosis - Damaged cells killed to prevent mutated gene transmission
- Cycle cycle control - Checkpoints during cell division to ensure cell is health & there is no damaged DNA
- Gene transcription regulation - Activation signals required to induce gene expression,.
18
Q
Mutation factors - 3
A
- Environmental factors: e.g. Chemicals (cigarette smoke), Radiation (UV exposure)
- Inherited Factors: e.g. mutations in germ-like DNA
- Viral Factors: e.g. Rous Sarcoma Virus, HPV - cervical cancer
19
Q
Aberrant gene mutations - 2
A
- Sequence insertions or deletions might scramble encoded mRNA leading to complete loss in function
- Could change amino acid, changing a proteins structure & function, can be beneficial or detrimental.
20
Q
Example of diseases caused by mutation - 3
A
- Cystic Fibrosis - 3 nucleotide deletion-loss of phenylalanine, incorrect folding leading to subsequent degradation - impaired mucosal clearance in lungs.
- Sick Cell Anaemia - Mutation of beta-globin gene - distortion of RBCs so they get stuck in vessels.
- X-SCID - Mutation in cytokine receptor signalling chain - immunodeficiency.
21
Q
RAS-MAPK signalling pathway -
A
- A growth factor receptor that activates a signalling pathway to the nucleus to switch on transcription of genes to drive the cell cycle.
- Once receptor is activated, Ras is activated by converting GDP → GTP - then releases a phosphate group to activate the Raf protein.
- Raf protein signals MAPK to increase gene transcription
22
Q
Oncogenes - 6
A
- Oncogenes: Mutated genes which control cell growth(proto-oncogenes).
- Is dominant
- Typically encode for growth factors, receptors, signal transducers or nuclear transcription factors.
- Point mutation in Ras-MAPK makes it become constitutively active.
- Causes Ras-MAPK to increase gene transcription.
- All self cells, immune system does not see it as foreign.
23
Q
Epidermal Growth factor - 4
A
- EGF is an important growth factor.
- Intrinsic kinase domain leading to activation of downstream signalling pathways - mutations in receptors can be in two ways:
- Ligand independent - constitutive dimerization
- or Overexpression - gene amplification
24
Q
Outline of the cell cycle & why its important for DNA integrity - 5
A
- G1 (Gap 1): The cell grows, performs normal functions, & prepares for DNA replication.
- S (Synthesis): DNA is replicated, ensuring the cell has two complete sets of chromosomes.
- G2 (Gap 2): The cell continues to grow, synthesizes proteins, & checks DNA for errors before division.
- Mitosis: The cell divides into two genetically identical daughter cells, which involves stages like prophase, metaphase, anaphase, & telophase.
- The stages ensure proper cell division & function, ensuring they are healthy & viable - with perfectly intact DNA.
25
Cell cycle regulation - 3
1. Cyclin & Cyclin Dependant Kinases (CDK) are regulatory proteins in the cycle - cyclin is activates CDK to regulate cell growth cycle points.
2. Upregulation of cyclins drive cell progression through each stage, once finished the cyclin is degraded to prevent backflow.
3. If damaged, the cell is signalled to die by apoptosis & the cell cycle is inhibited - except in the presence of cancer causing the loss in function of genes driving apoptosis.`
26
How do translocations affect genes - 2
1. Aberrant cross over of chromosomes can change a gene to be regulated by a different promoter than usual
2. This can dysregulate gene expression, leading to alterations in cell growth.
27
Causes of lung cancer - 2
1. Most commonly caused by environmental carcinogens.
2. Benzopyrene in cigarette smoke is metabolised in the liver generating a potent mutagen which causes G > T transversions in DNA
28
Lung cancer treatment - 3
1. Chemotherapy - cytotoxic drugs
2. Targeted therapies – EGFR inhibitors
3. Iressa (Gefitinib) – only active in hypermutated EGFR
29
Transcriptional regulation - 2
1. Controls expression of genes in a temporal & spatial manner.
2. Ensures different areas of the body, brain & skin activate the correct transcriptional factors.
30
Requirements of transcriptions - 3
1. RNA polymerase
2. DNA template
3. Promoters.
31
Promoter region - 5
1. The DNA sequence that determines the site of transcription initiation for an RNA polymerase.
2. Composed of sets of conserved DNA sequences.
3. Ensures the right RNA is at the right gene.
4. Present in DNA upstream of transcriptional start site
5. Recognised by transcription factors & RNA polymerase.
32
Introns & Exons - 3
1. Exon regions are the coding region
2. Introns are non coding.
3. Introns cut out so the gene can be spliced in different ways to form polymorphisms.
33
Transcription control elements - 5
1. RNA polymerase binds to the TATA box to ensure transcribing begins.
2. The enhancer to TATA box is the promoter region.
3. The enhancer region causes specificity.
4. By binding different transcription factors the transcription & timing of genes is controlled.
5. They bind by recognising sequences within the DNA.
34
Activation of gene transcription process
Driven by availability/ activation of transcription factors & accessibility of DNA.
35
Effect of histone acetylation - 5
1. Histone proteins contain many basic amine acids (+ve charges at cellular pH)
2. Enables interaction with -ve phosphate backbone of DNA
3. The acetylation blocks ability to bind DNA by masking +ve charge, relaxing interaction of DNA w/ nucleosome, increasing accessibility & hence transcription.
5. Coactivators have Histone Acetyltransferase activity - add acetyl groups to histones.
36
Chromatin types - 2
1. Heterochromatin: Densely packed nucleosomes that are not actively transcribed & are acetylated histones.
2. Euchromatin: Extended appearance like beads on a string, are actively transcribed & are acetylated histones.
37
Methylation's effects on chromatin
Methylation causes genes to be rewound tighter to become transcriptionally inert.
38
Signal transduction steps - 4
1. Stimulus e.g. growth factors, hormone
2. Receptor e.g. tyrosine-kinase linked, ion channels
3. Cascades e.g. kinase activation, phosphorylation
4. Response e.g. gene expression, growth development
39
Transcription - 15
1. Ligand activates receptor
2. Activation of intracellular signalling pathway (kinases & second messengers)
3. Activation of inducible transcription factors
4. Recruitment of coactivator proteins
5. Unwinding of DNA in enhancer region
6. Binding of inducible factors
7. Looping of DNA
8. Unwinding of DNA in upstream region (CAAT/ GC box)
9. Binding of constitutive factors
10. Looping of DNA
11. Coactivator enhances binding of TBP to TATA box
12. Cooperative binding of other basal factors & RNA polymerase II
13. Activation of RNA Polymerase II, the rate limiting step
14. Unwinding of DNA & reading 3’ to 5’ DNA strand
15. Synthesis of mRNA 5’ to 3’
40
Control of gene accessibility - 2
1. Accessibility determined by chromatin structure - the winding of DNA around a histone protein.
2. Requires Coactivator proteins to unwind DNA.
41
Histone deacetylation
Histone deacetylation is carried out by HDACs (histone de-acetylases), exposing the positive charge to re-enable winding.
