Mutation and DNA repair mechanism
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Mutations occur through endogenous and exogenous DNA damage and can be in the form of point mutations, frame shifts, or splicing errors. Mutation types include nonsense mutations which result in premature stop codons, missense mutations which code for different amino acids, and silent mutations which do not change the amino acid. Frameshift mutations change the reading frame by inserting or deleting nucleotides. Splicing errors can occur from mutations affecting splice sites or their specificity. Lethal mutations cause death while loss or gain of function mutations impact gene activity.
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Mutation and DNA repair mechanism
- 1. Addis Ababa University School of Medicine Department of Biochemistry Advanced Molecular Biology Seminar Mutation and DNA repair Mechanism by Ayetenew Abita Wednesday December 20, 2017GC7/31/2019 1
- 2. OUTLINE • Introduction • Causes of mutation • Point mutation • Frame shift mutation • Abnormal intron removal and exon splicing • Summary • Reference7/31/2019 2
- 3. INTRODUCTION • The blue print of genetic information • The master plan of genetic information • The genetic database Is stored in the nucleus as DNA 7/31/2019 3
- 4. INTRODUCTION DNA damage •Mutation is a permanent change DNA sequence or changed in the genetic message carried by gene. •Mutagen is an agent that can bring about a permanent alteration to the physical composition of a DNA gene. •Damaged mRNA lead to altered polypeptide sequence.7/31/2019 4
- 5. CAUSE OF DNA MUTATION Mutations occur continuously through endogenous and exogenous DNA damage. Examples of endogenous DNA damage: Reactive oxygen species (ROS), DNA replication errors. Examples of exogenous DNA damage: tobacco carcinogens, toxins in food, pollution, ultraviolet light from the Sun, gamma and X- radiation, medications, viruses. 7/31/2019 5
- 6. TAUTOMERISATION • The bases of DNA are subject to spontaneous structural alterations called tautomerisation. •Some of the hydrogen atoms change their location producing a tautomer •An amino group (-NH2) can tautomerise to an imino form (=NH) •A keto group (-C=O) can tautomerise to an enol form (=C-OH) Ex: Thymine (keto form) shifts to enol form , which pairs with guanine. 7/31/2019 6
- 7. CAUSE OF DNA MUTATION 7/31/2019 7
- 8. UV (Ultraviolet) • UV is normally classified in terms of its wavelength: UV-C (180-290 nm)--"germicidal"--most energetic and lethal, it is not found in sunlight because it is absorbed by the ozone layer. UV-B (290-320 nm)--major lethal/mutagenic fraction of sunlight. UV-A (320 nm visible)"near UV“ also has deleterious effects primarily because it creates oxygen radicals, but it produces very few pyrimidine dimers. 7/31/2019 8
- 9. CAUSE OF DNA MUTATION 7/31/2019 9
- 10. Base Analog Bromouracil (structural analog of Thymine) Enzyme of nucleotide synthesis and DNA synthesis treat Bromouracil as thymine and incorporate it into DNA , where it pairs with adenine. 7/31/2019 10
- 11. Alkylation Agent • Alkylating agents are chemicals that add bulky chemical groups like methyl (CH3) and ethyl (CH2-CH3) chains to bases • Ethyl methansulfonate (EMS) is such an alkylating agent • The addition of ethyl group distorts the helix and leads to incorrect base pairing.. 7/31/2019 11
- 12. Deaminating agents Deaminating agents are chemicals that remove amino groups • Adenine deamination with nitrous acid produces hypoxanthine, which can mispair with cytosine, inducing a TC mutation 7/31/2019 12
- 13. CAUSE OF DNA MUTATION 7/31/2019 13
- 14. THE EFFECTS OF MUTATIONS • Some mutations cannot be passed on to offspring and do not matter for evolution. • Somatic mutations occur in non-reproductive cells and won't be passed onto offspring. • The only mutations that matter to large-scale evolution are those that can be passed on to offspring. • These occur in reproductive cells like eggs and sperm and are called germ line mutations. 7/31/2019 14
- 15. EFFECTS OF GERM LINE MUTATIONS • A single germ line mutation can have a range of effects • No change occurs in phenotype. Some mutations don't have any noticeable effect on the phenotype of an organism. • The mutation occurs in a protein-coding region, but ends up not affecting the amino acid sequence of the protein. • Small change occurs in phenotype. • Big change occurs in phenotype. Mutations that cause the death of an organism are called lethals. • Little mutations with big effects: Mutations to control genes 7/31/2019 15
- 16. EFFECTS OF GERM LINE MUTATIONS • 7/31/2019 16
- 17. TYPES OF DNA MUTATION 7/31/2019 17
- 18. Point mutation • A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a sequence of DNAor DNA. • Point mutation is a random SNP (single nucleotide polymorphism ) mutation in the deoxyribonucleic acid ( DNA) that occurs at one point. 7/31/2019 18
- 19. Transition/transversion categorization In 1959, Ernst Freese • Transition Mutations (Alpha) are due to replacement of a purine base with another purine or a pyrimidine with another pyrimidine. • Transversions Mutations (Beta) are replacement of a purine with a pyrimidine or vice versa. • Transition mutations are about ten times more common than transversions. 7/31/2019 19
- 21. Functional Categorization 1) Nonsense Mutations a)Stop-gain is a mutation that results in a premature termination codon (a stop was gained), which signals the end of translation. This interruption causes the protein to be abnormally shortened. b) Stop-loss is a mutation in the original termination codon (a stop was lost), resulting in abnormal extension of a protein's carboxyl terminus. c)Start-gain creates a TAC start codon upstream of the original start site. d) Start-loss is a point mutation in a transcript's TAC start codon, resulting in the reduction or elimination of protein production. 7/31/2019 21
- 22. 1) Nonsense Mutation Examples of truncated protein formed in nonsense mutation converts an amino acid codon into a termination codon. 7/31/2019 22
- 23. 2)Missense Mutations Code for a different amino acid. A missense mutation changes a codon so that a different protein is created, a non-synonymous change. a) Acceptable mutation Eg: Normal Hemoglobin A molecule , 67th amino acid in beta chain 7/31/2019 23
- 24. 2)Missense Mutations b) Partially acceptable: Partially functional protein Example Sickle cell anemia ( HbS) 7/31/2019 24
- 25. 2)Missense Mutations .c) Unacceptable Mutation Incompatible with normal life Eg : HbM Distal histidine of alpha chain 7/31/2019 25
- 26. 3) Silent mutations • Since the genetic code are redundant single nucleotide can change, but the new codon specifies the same amino acid, resulting in an unmutated protein. • A silent mutation has no effect on the functioning of the protein. • This type of change is called synonymous change, since the old and new codon code for the same amino acid. This is possible because 64 codons specify only 20 amino acids. 7/31/2019 26
- 28. FRAMESHIFT MUTATION • Inserting or deleting one or more nucleotides Changes the “reading frame” like changing a sentence Proteins built incorrectly • A frameshift mutation is not the same as a single-nucleotide polymorphism in which a nucleotide is replaced, rather than inserted or deleted. 7/31/2019 28
- 30. Splicing Errors • Mutation of a splice site resulting in loss of function of that site. Results in exposure of a premature stop codon, loss of an exon, or inclusion of an intron. • Mutation of a splice site reducing specificity. May result in variation in the splice location, causing insertion or deletion of amino acids, or most likely, a disruption of the reading frame. • Displacement of a splice site, leading to inclusion or exclusion of more RNA than expected, resulting in longer or shorter exons. • Although many splicing errors are safeguarded by a cellular quality control mechanism termed nonsense-mediated mRNA decay (NMD), a number of splicing-related diseases also exist . 7/31/2019 30
- 31. SUMMARY • Mutations occur continuously through endogenous and exogenous DNA damage • Mutation might be point, frame shift, splicing error. • lethal mutation: causes the developing organism to die prematurely. • loss-of-function mutation: either reduces or abolishes the activity of the gene. • gain-of-function mutation: increases the activity of the gene or makes it active in inappropriate circumstances . 7/31/2019 31
- 32. REFERENCE • Harper’s Review of Biochemistry • Lehniger’s principle of Biochemistry • Lippincott’s Illustrated Review of Biochemistry • Text Book of Biochemistry with clinical correlations- Devlin TM • Text Book of Biochemistry by Vasudevan • Text book of biochemistry, satyanarayana • Principle of biochemistry, William H. simmons. 7/31/2019 32
- 33. • 7/31/2019 33
Editor's Notes
- DNA repair mechanism Mismatch repair Base excision repair Nucleotide excision repair Double stranded break repair Summary
- A Mutation occurs when a DNA gene is damaged or changed in such a way as to alter the genetic message carried by that gene.A Mutagen is an agent of substance that can bring about a permanent alteration to the physical composition of a DNA gene such that the genetic message is changed. Once the gene has been damaged or changed the mRNA transcribed from that gene will now carry an altered message. The polypeptide made by translating the altered mRNA will now contain a different sequence of amino acids. The function of the protein made by folding this polypeptide will probably be changed or lost. In this example, the enzyme that is catalyzing the production of flower color pigment has been altered in such a way it no longer catalyzes the production of the red pigment. No product (red pigment) is produced by the altered protein. In subtle or very obvious ways, the phenotype of the organism carrying the mutation will be changed. In this case the flower, without the pigment is no longer red
- Spontaneous tautomeric shifts in the bases contribute to replication errors Ex: Thymine (keto form) shifts to enol form , which pairs with guanine
- Spontaneous tautomeric shifts in the bases contribute to replication errors Ex: Thymine (keto form) shifts to enol form , which pairs with guanine
- The major lethal lesions are pyrimidine dimers in DNA (produced by UV-B and UV-C)--these are the result of a covalent attachment between adjacent pyrimidines in one strand.
- Mutagenic component of sunlight Can not penetrate beyond the outer layer of the skin and - unable cause germ line mutations. only causes sunburn and skin cancer mainly through the formation of pyrimidine dimers
- 1. Base analog Bromouracil (structural analog of Thymine) Enzyme of nucleotide synthesis and DNA synthesis treat Bromouracil as thymine and incorporate it into DNA , where it pairs with adenine
- printDNA and Mutations : The effects of mutations Since all cells in our body contain DNA, there are lots of places for mutations to occur; however, some mutations cannot be passed on to offspring and do not matter for evolution. Somatic mutations occur in non-reproductive cells and won't be passed onto offspring. For example, the golden color on half of this Red Delicious apple was caused by a somatic mutation. Its seeds will not carry the mutation.The only mutations that matter to large-scale evolution are those that can be passed on to offspring. These occur in reproductive cells like eggs and sperm and are called germ line mutations. Effects of germ line mutations A single germ line mutation can have a range of effects: No change occurs in phenotype. Some mutations don't have any noticeable effect on the phenotype of an organism. This can happen in many situations: perhaps the mutation occurs in a stretch of DNA with no function, or perhaps the mutation occurs in a protein-coding region, but ends up not affecting the amino acid sequence of the protein. Small change occurs in phenotype. A single mutation caused this cat's ears to curl backwards slightly. Big change occurs in phenotype. Some really important phenotypic changes, like DDT resistance in insects are sometimes caused by single mutations. A single mutation can also have strong negative effects for the organism. Mutations that cause the death of an organism are called lethals — and it doesn't get more negative than that. Little mutations with big effects: Mutations to control genes Mutations are often the victims of bad press — unfairly stereotyped as unimportant or as a cause of genetic disease. While many mutations do indeed have small or negative effects, another sort of mutation gets less airtime. Mutations to control genes can have major (and sometimes positive) effects. Some regions of DNA control other genes, determining when and where other genes are turned "on". Mutations in these parts of the genome can substantially change the way the organism is built. The difference between a mutation to a control gene and a mutation to a less powerful gene is a bit like the difference between whispering an instruction to the trumpet player in an orchestra versus whispering it to the orchestra's conductor. The impact of changing the conductor's behavior is much bigger and more coordinated than changing the behavior of an individual orchestra member. Similarly, a mutation in a gene "conductor" can cause a cascade of effects in the behavior of genes under its control. Many organisms have powerful control genes that determine how the body is laid out. For example, Hox genes are found in many animals (including flies and humans) and designate where the head goes and which regions of the body grow appendages. Such master control genes help direct the building of body "units," such as segments, limbs, and eyes. So evolving a major change in basic body layout may not be so unlikely; it may simply require a change in a Hox gene and the favor of natural selection.
- lethal mutation: causes the developing organism to die prematurely. conditional mutation: produces its phenotypic effect only under certain conditions, called the restrictive conditions. Under other conditions—the permissive conditions—the effect is not seen. For a temperature-sensitive mutation, the restrictive condition typically is high temperature, while the permissive condition is low temperature. loss-of-function mutation: either reduces or abolishes the activity of the gene. These are the most common class of mutations. Loss-of-function mutations are usually recessive—the organism can usually function normally as long as it retains at least one normal copy of the affected gene. null mutation: a loss-of-function mutation that completely abolishes the activity of the gene. gain-of-function mutation: increases the activity of the gene or makes it active in inappropriate circumstances; these mutations are usually dominant. dominant-negative mutation: dominant-acting mutation that blocks gene activity, causing a loss-of-function phenotype even in the presence of a normal copy of the gene. This phenomenon occurs when the mutant gene product interferes with the function of the normal gene product. suppressor mutation: suppresses the phenotypic effect of another mutation, so that the double mutant seems normal. An intragenic suppressor mutation lies within the gene affected by the first mutation; an extragenic suppressor mutation lies in a second gene—often one whose product interacts directly with the product of the first
- the oxygen caring capacity of Hb is lost in this cases.
- Codons are redundant
- Recall that genetic code is non-overlapping or comma-less
- Recall the post transcriptional modification.