Topic 6 - DNA Mutations bc1bc5c29756431db1697c43e0d17a6a.pdf

💱 Topic 6 - DNA Mutations Lecture 1 Define Mutation a randomly derived change to the nucleotide sequence of the genetic material of an organism, causing a biological effect...

💱 Topic 6 - DNA Mutations Lecture 1 Define Mutation a randomly derived change to the nucleotide sequence of the genetic material of an organism, causing a biological effect 3 Causes of Mutations Spontaneous: Damage caused by chemical instability of DNA components Environmental: DNA damage from environmental physical or chemical agents (e.g. UV, chemical mutagens) Genetic Events: Re-arrangements (e.g. recombination exchange of DNA between chromosomal segments), DNA replication Importance of DNA Repair, Describe the steps of the P50 repair mechanism DNA is the only biological macromolecule that is repaired. All others are replaced. Topic 6 - DNA Mutations 1  P50 Repair mechanism damage detected increased p50 protein in cell ensures damaged DNA + proteins are not replicated p50 induces genes → apoptosis coordinates response between cell cycle + DNA Repair What is the difference between Apoptosis and Necrosis Apoptosis = programmed cell death, outer membrane is still intact and functions Necrosis = caused by physical destruction to the cell membrane by bacteria, cell loses control, cell, membrane & its contents are all destroyed. what is the physiological function of apoptosis elimination of damaged/unwanted cells form finger/toes remove harmful immune cells Spontaneous base loss random loss of bases, forming AP Sites Spontaneous deamination removal of an Amino group from the base induced by chemical mutagens (nitrous acid) - C to U happens in the liver “Reactive Oxygen Species” (ROS) addition of an O, O2, HOOH, or OH group to a base affects DNA Base pairing ability, leads to unwinding/breakdown of DNA molecules Topic 6 - DNA Mutations 2  what mutation can UV radiation cause formation of dimers between adjacent bases energy from UV forms a covalent bond between adjacent bases, inhibits base pairing what mutation can smoking lead to benzo[a]pyrene - the major mutagen in tobacco smoke, and DNA. leads to insertion and covalent bond formation between benzo[a]pyrene and DNA in the middle of DNA ladder disrupts base pairing & overall DNA structure what mutations does Ionising radiation cause single strand breaks - defect in one of the two strands double stranded breaks - defects within both DNA strands Topic 6 - DNA Mutations 3  base damage crosslinks - covalent bond formation between bases within intrastrands (within same strands) or interstrand (diff strands) What are the 3 types of DNA Repair with examples Direct reversal of damage (Photoreactivation) Excision Strand break repair – repairing the DNA backbone Photoreactivation directly reversing the formation of pyrimidine dimers using a photolyase enzyme what are the 3 Excision repair pathways Takes advantage of the double-stranded (double information) nature of the DNA molecule. Nucleotide excision repair damage detected by enzyme undamaged DNA remains + DNA polymerases uses it as a template to synthesise a short complimentary sequence DNA ligase sticks the 2 strands to form a double stranded nature Topic 6 - DNA Mutations 4  Base excision repair removing damaged bases that would otherwise cause mutations initiated by DNA glycosylases which recognise and remove specific damaged/inappropriate bases forms AP sites, which polymerase binds to for synthesis of nucleotides DNA Mismatch repair system for recognising/repairing insertion, deletion and mis-incorporation of bases that occur during DNA replication Topic 6 - DNA Mutations 5  Non-homologous end joining repair NHE repair system: Repairs DNA by joining broken ends of the chromosome without a template. Enzymes quickly bind and weld DNA pieces together to complete the molecule. Before binding, processing involves removing damaged or mismatched nucleotides with nucleases and resynthesizing with DNA polymerases. Non-homologous end joining repairs DNA by directly re-joining the two broken ends of the chromosome. it can result in the loss or occasional addition of a few nucleotides at the cut site. Non-homologous end joining often leads to mutations. Homologous recombination Topic 6 - DNA Mutations 6  Homologous recombination uses information from a matching homologous chromosome or sister chromatid to repair DNA breaks. The process involves bringing together two homologous chromosomes. The undamaged region of the homologous chromosome or chromatid serves as a template to replace the damaged region of the broken chromosome. does not usually cause mutations. Radiation Damage erythemia (skin-reddening), necrosis (death) of exposed tissue, eye irritation Ionising radiations damage all biomolecules (including DNA) similarly. Bond-breaks occur either: - Directly, by direct ionisation of the biomolecule Indirectly, through the ionisation of water, and the formation of damaging reactive radicals Radiation does not produce new, unique mutations, but simply increases the incidence of the same mutations that occur spontaneously Topic 6 - DNA Mutations 7  Lecture 2 Point mutations causes insertion/deletion of bases Transition purine → purine Transversion Transversion - purine ⇌ pyrimidine Frameshift deletion or insertion (addition of a nucleotide) in a DNA sequence that shifts the way the sequence is read non-sense introduction of a stop codon missense one base changes → changes in code for a different amino acid redundancy multiple codons code for a single amino acid Sickle Cell Anaemia Change in the shape of haemoglobin protein folding, leading to a change from a red blood cell to a sickle cell change in amino acid from glutamic acid to valine chromosome 11 Achondroplasia Topic 6 - DNA Mutations 8  Disease - dwarfism Missense mutation in FGFR3 (fibroblast growth factor receptor 3) on chromosome 4p in humans Arginine is produced instead of glycine production of arginine enhances gene function and no. of FGFR3 signals released Mitosis is promoted, but cell differentiation is depressed due to enhancement of gene function Inhibits proliferation and differentiation → reduced bone growth Phenylketonuria (PKU) Metabolic disorder due to a lack of phenylalanine breakdown. Problem lies with faulty phenylalanine hydroxylase (PAH), which converts phenylalanine into tyrosine. Caused by a single change (G to A) on chromosome 12, resulting in a premature stop codon. High level of phenylalanine in the blood due to this deficiency leads to neurological problems. Diet restrictions: no milk, dairy, meat, fish, chicken, eggs, or beans. Cystic Fibrosis Cystic Fibrosis (CF) caused by mutations in both copies of CFTR gene. It's an autosomal recessive condition; one mutated gene won't show symptoms. CFTR controls sweat, digestive fluids, and mucus production. Malfunctioning CFTR leads to thick secretions. Affects lungs, pancreas, sweat glands, and sometimes other organs. Treatments include: Digestive enzyme and nutritional supplements. Lung percussion, drainage, and antibiotics. Topic 6 - DNA Mutations 9  Inhaled medications via aerosols. Huntington’s Disease Huntington's Disease (HD) is an inherited disorder. It leads to brain cell death and jerky body movements. Typically appears between 30-50 years, with a 15-25 year survival after symptoms start. Symptoms include irritability, depression, involuntary movements, poor coordination, and cognitive problems. HD is caused by a gene mutation with too many CAG repeats. Autosomal dominant mutation The mutation occurs on chromosome 4p16.3. What are the advantages of gene cloning using animals Experimental animal models are inbred and therefore genetically homogenous (similar) Well controlled environment Faster reproduction rate DNA Mutations Topic 6 - DNA Mutations 10