Mutation PDF - DNA Mutations and Repair

# Mutation ## What are mutations? - Any changes in the DNA sequence of an organism is a mutation. - DNA is made of a long sequence of smaller units strung together. There are four basic types of unit: A, T, G, and C. - Some parts of DNA are control centers for turning genes on and off. - Some par...

# Mutation ## What are mutations? - Any changes in the DNA sequence of an organism is a mutation. - DNA is made of a long sequence of smaller units strung together. There are four basic types of unit: A, T, G, and C. - Some parts of DNA are control centers for turning genes on and off. - Some parts have no function. - And some parts have a function that we don't know yet. - Organisms have mechanisms such as DNA repair to remove mutations. ## Types of mutations - Mutation - Point mutation - Transition - Transversions - Frame shift mutation - Insertions - Deletions ## Common defects in DNA and Their Origins | Type of Defect | How Does This Type of Change Arise? | |:------------------------|:-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | 1. Incorrect base in one strand cannot hydrogen bond with corresponding base in the opposite strand | Normal base tautomerizes (i.e., isomerizes in such a way that is capable of an alternative form of hydrogen bonding); base substitution occurs during subsequent DNA replication | | 2. Missing bases | Depurination: N-glycosylic bond joining puine base to deoxy-ribose is spontaneously broken without breaking DNA backbone | | 3. Altered bases | Alkylating agents add methyl or ethyl groups to existing bases | | 4. Addition or deletion of one or more bases | May occur spontaneously, or be induced by chemical mutagens (intercalating agents) or biological agents (transposable elements) | | 5. Single-strand breaks | Phosphodiester bond is broken as a result of exposure to chemical agents or ionizing, radiation | | . Double-strand breaks | Phosphodiester bonds on opposite DNA strands are broken as a result of exposure to high doses of chemical agents or ionizing radiation | | Cross-linking of complementary DNA strands | Certain antibiotics (mitomycin-C) or reagents (nitrite ions) form covalent bonds between two bases on complementary DNA strands, preventing strand separation during DNA replication | ## Types of DNA damage: Base loss and base modification ### Chemical Modification - Thymine - Adenine - Cytosine - Guanine ### Depurination - AP site ### Photodamage thymine dimer <h3> Deamination</h3> - Cytosine - Uracil <h3> Chemical Modification by O₂ free radicals</h3> - Cytosine - Uracil ## Common and Rare forms of bases ### Thymine - Common: Keto form - Rare: Enol form ### Cytosine - Common: Amino form - Rare: Imino form ### Adenine - Common: Amino form - Rare: Imino form ### Guanine - Common: Keto form - Rare: Enol form ## Causes of mutations - **Spontaneous mutations:** Tautomeric shifts - Tautomeric shifts immediately prior to DNA replication causes a mismatch that could be repaired. - If repair system fails, a mutation may result. ## Depurination - Release of adenine or guanine bases ## Mutations, Mutagenesis, and DNA Repair ### Examples of Types of Point Mutations | Type of Mutation  | Result at Molecular Level | Example | |:---------------------------------------------------|:----------------------------------------------------------------------------------------------------------------------------|:-----------------------| | A. Base Substitution Mutations:  | |:-----------------------| | Changes in DNA | |:-----------------------| | 1. Transition:  | One purine replaced by a different purine; or one pyrimidine replaced by a different pyrimidine. | A→T,  G→C | | 2. Transversion:  | A purine replaced by a pyrimidine or vice versa. | A→T,  A→T,  T→A | | Changes in protein | |:-----------------------| | 1. Silent mutation:  | Altered codon codes for same amino acid. | GAGGAA,  Glu→Glu | | 2. Neutral mutation:  | Altered codon codes for a different but functionally similar amino acid. (Protein may be functional.) | GAGGAU,  Glu→Asp | | 3. Missense mutation:  | Altered codon codes for a different, dissimilar amino acid. (Protein often nonfunctional.) | GAGAAG,  Glu→Lys | | 4. Nonsense mutation (= Chain termination mutation): | New codon is a termination codon. (Protein synthesis stops. Protein is nonfunctional.) | GAGUAG,  Glu→Stop | | B. Frameshift Mutations: Addition or deletion of one or more base pairs will result in a shift in the reading frame of the resulting mRNA molecule, and lead to production of a nonfunctional protein. | |:-----------------------| | 1. Wild type base sequence:  | ATG ACC AGG TC | | | 2. Base addition:  | ATG ACA CAG GTC | | | 3. Base deletion:  | ATG ACA GGT C | | ## Frameshift mutations - A frameshift mutation is a genetic mutation caused by indels (insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. This type of mutation can change the reading frame of a gene, resulting in a different amino acid sequence or a premature stop codon. ## Causes of mutations - **Tautomeric transitions:** - A tautomeric shift is a change in the structure of a base that can result in the mispairing of bases during DNA replication. - For example, a tautomeric shift in adenine can cause it to pair with cytosine instead of thymine. - **Depurination:** - Loss of purine bases - It can lead to a deletion of a base pair if not repaired. - **Alkylation:** - Alkylating agents add alkyl groups to the nucleotide bases, which can interfere with base paring. - Examples include nitrogen mustard, ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS). - **Intercalating agents:** - Intercalating agents are flat molecules that insert themselves between the base pairs of DNA, which can distort the DNA helix and lead to frameshift mutations. - Examples include acridine orange, ethidium bromide and proflavin. ## Deamination - Involves the removal of a amino group from the cytosine base. - Other bases aren't readily deaminated, like uracil. - DNA repair enzymes can recognize uracil as an inappropriate base and remove it. - However, if this repair system fails, a C-G to A-T mutation will result. ## Hydroxylamine - It's known as a base modifying mutagen. - It converts cytosine into hydroxylaminocytosine. - It increases the frequency of this rare tautomer. - It leads to CG:TA transitions. - It only affects cytosine, so it won't generate TA:CG transitions. ## Induced mutations arise from damaged DNA caused by chemicals and radiation - **Alkylating agents:** These agents add alkyl groups (like methyl or ethyl) to the purine or pyrimidine of the nucleotide. - `Mustard gas` is one example, as it adds alkyl groups to Guanine. - **Intercalating agents:** They wedge themselves between the base pairs of DNA. - They cause single nucleotide insertions and deletions. - **Agents that promote oxidative damage to DNA:** These agents can damage DNA by producing reactive oxygen species (ROS) that can cause mutations. ## Mutagens | Class | Mutagen | |:-----------------------------|:------------------------------------------------------------------------------------| | **Physical mutagens** | | | 1. Ionizing radiations | -Alpha, beta, fast neutrons, thermal neutrons, X-rays, gamma rays, UV rays | | 2. Non-ionizing radiations | | | **Chemical mutagens** | | | 1. Alkylating agents | -Mustard gas, nitrogen mustard, EMS, MMS, EES.            | |                               | 5-Bromouracil, 2-amino purine, acriflavin, proflavin, acridine orange.                      | | 2. Deamination agents | -Nitrous acid (HNO2), hydroxylamine, sodium azide | ## Mutagenesis, Biological Mutagens and Metals | Physical Mutagens | Chemical Mutagens | Biological Mutagens | Metals | |:-------------------|:------------------------------------------|:------------------------|:-------------| | X-rays | Reactive oxygen species (ROS) | Transposons | Arsenic | | | Deaminating agents such as nitrous acid | Viruses | Chromium | | Gamma rays | Alkylating agents such as nitrosamines | Bacteria | Cadmium | | | and ethylnitrosourea | Prions | Nickel | | Alpha rays | Aromatic amines and amides | | | | | Alkaloids from plants | | | | Ultraviolet radiations | Bromine, benzene and sodium azide | | | | Radioactive decay | | | | | Cosmic rays | | | | ## Summary: This document discusses mutations and their causes. It starts by explaining what a mutation is and describes different types of mutations. The document goes on to describe common defects in DNA and their origins, including incorrect bases, missing bases, altered bases, addition or deletion of bases, single-strand breaks, double-strand breaks and cross-linking of complementary DNA strands. It then lists different types of DNA damage, including base loss and base modification, and provides examples of each type of damage. The document also discusses the causes of mutation, including tautomeric shifts, depurination, alkylation, and intercalating agents. It then goes into detail about deamination and hydroxylamine. Finally, it discusses induced mutations in DNA that are caused by chemicals and radiation. The document then explains the role of alkylating agents in causing mutations.