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Mutations & DNA Repair. What are mutations? Mutagenesis: Process of producing a mutation Repair of mutations. Mutations can cause changes in the shape of a protein which alters its function. What are mutations?. Classes of mutations:

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Mutations dna repair
Mutations & DNA Repair

  • What are mutations?

  • Mutagenesis: Process of producing a mutation

  • Repair of mutations

What are mutations
What are mutations? alters its function.

  • Classes of mutations:

  • Spontaneous mutation - occurs in nature without the addition of a mutagen

  • Induced mutation – caused by a mutagen

  • Point mutation – change of 1 nucleotide

  • Insertion/Deletion – base added or deleted

  • Frameshift mutation – loss or addition of a nucleotide alters the codon reading frame

  • Forward mutation – converts wild type to mutant

  • Reverse mutation – converts mutant back to wild type

  • Loss of function mutation

  • Gain of function mutation

Base substitutions point mutations
Base substitutions/Point mutations alters its function.

  • Transitions

    • Purine replaced by a purine… or pyrimidine replaced by a pyrimidine

  • Transversions

    • Purimidine replaced by a purine, or vise versa

    • Less common… why?

T & C

A & G

Additional mutational categories
Additional mutational categories: alters its function.

  • Lethal mutation – results in death

  • Conditional mutation – expression depends on the environment

    • i.e. temperature sensitive mutations

  • Somatic mutation – not transmitted to future generations

  • Germinal/gametic mutation – transmitted to offspring

Mutational outcomes
Mutational outcomes alters its function.

  • Silent substitution – function of the protein product of gene is unaltered

  • Missense mutation – alters codon so that it encodes a different amino acid

  • Nonsense mutation – alters gene so that it creates a nonsense codon (no normal tRNA exists) causing termination of translation

Spontaneous mutations
Spontaneous mutations alters its function.

  • Spontaneous mutations arise from replication errors & base modifications

  • DNA Replication errors

    • Replication slippage – one strand loops out and becomes displaced during replication

    • DNA pol stuttering

    • Occurs frequently in repeat regions: Hot Spots for DNA mutation

  • Spontaneous mutation rate various among organisms (table 15.2)

Ways Mutations can occur: alters its function.

-Replication Error

-Breaks in DNA strands

-Damage to nucleic acids

-Mobile elements

II. Mutagenesis: Process of producing a mutation

Induced mutation mechanisms
Induced Mutation Mechanisms alters its function.

  • Base replacement

  • Base alteration

  • Base damage

1 base replacement
1. Base replacement alters its function.

  • Base analogs(chemicals that are similar to nucleotides) substitute themselves for the nucleotide

  • Result = improper base pairing

  • Examples:

    a) Tautomeric Shifts - Tautomerization – isomerization of a nitrogen base to an alternative H-bonding condition

    b) Chemicals:

    5-Bromocuracil (T analog),

    2-Aminopurine (A analog)

Tautomerization – Known as a tautomeric shift alters its function.

“rare” forms result in mispairing,


Mispairing results in replication errors – the wrong bases are incorporated into the daughter strands

5 BU (derivative of uracil) behaves as a thymine analog, if 5 BU is incorporated it will base pair with guanine, after 1 round of replication an A-T to G-C transition results

2 base alteration
2. Base alteration 5 BU is incorporated it will base pair with guanine, after 1 round of replication an A-T to G-C transition results

  • Chemicals cause the shape of the nucleotide to change, resulting in improper base pairing

    • Depurination (loss of nitrogenous base) & Deamination (amino group converted to keto group)

  • Alkylation – addition of alkyl group (CH3 or CH3CH2) to bases

    • EMS (ethylmethane sulfonate)

  • Intercalation – planer molecules that mimic base pairs and slip themselves between the stacked nitrogen bases at the core of the helix

    • Ethidium bromide

    • Proflavin

    • Acridine orange

Intercalating agents slip between the nitrogenous bases, which can lead to insertion/deletions.

Frameshift mutations result – generated at gaps produced in DNA during replication

3 base damage
3. Base damage which can lead to insertion/deletions.

  • Chemicals, oxidation, radiation cause the nucleotide to become modified in such a way that it can no longer base pair

  • UV light

    • Results in pyrimidine dimers

  • Radiation

    • Causes ionization of molecules

    • Creates substitutions

    • Breaks phosphodiester bonds

Spontaneous mutation s arise due to natrual biological chemical processes
Spontaneous Mutation which can lead to insertion/deletions.s– arise due to natrual biological/chemical processes:

  • DNA replication errors

    • DNA replication errors = each of the bases can appear in one of several forms called tautomers (isomers)

  • Spontaneous lesions

    • Depurination - Apurinic sites can’t specify a base complementary to the original

    • Deamination = ie deamination of C yields U, which will pair w/A leading to a GC to AT transition

    • Oxidative damage – superoxide radicals (byproducts of metabolism) alter bases to cause mispairing… 8-oxidG or GO pairs with A

  • Transposable elements

    • significant part of the genome consists of “nomadic” DNA sequences that are present at different locations

Iii repair of mutations
III. Repair of mutations which can lead to insertion/deletions.

  • Direct Reversal of damage

  • Excision repair

  • Proofreading

  • Mismatch repair

  • Post-replication repair & SOS

  • Double-strand break repair

1 direct reversal of damage
1. Direct reversal of damage which can lead to insertion/deletions.

Photoreactivation repair: reversal of UV damage

  • Photolyase splits Thymine dimers, restoring DNA to its original condition

  • Photolyase works with cofactor folic acid

  • The two bind together in dark to T-dimer

  • When light shines on cell –folic acid absorbs the light & uses the energy to break the covalent bond between T’s

    O6-mGua DNA methyltransferase

    Alkyltransferase – one time repair enzyme that removes ethyl or methyl groups from guanine

  • 2 excision repair
    2. Excision repair which can lead to insertion/deletions.

    Involved in repair of deamination and depurination

    Enzymes recognize an abnormal base and cleave the bond between in and the sugar in the DNA backbone.

    • Uracil N-glycosylase

      • removes uracil

    • AP endonuclease

      • cuts 5’ side of damaged site on apurinic bases

    • Phosphodiesterase

      • Removes sugar-phosphate residue

    deamination which can lead to insertion/deletions.






    Uracil N-clycosylase






    Pol I

    3 proofreading
    3. Proofreading which can lead to insertion/deletions.

    DNA Pol III error rate: 10-5

    • Proofreading ability: Pol II can recognize mismatched base pairs, determine which base is the incorrect one excise the wrong base and carry out repair synthesis

    • 3’ to 5’ exonuclease ability, lowering the error rate to 10-7

    4 mismatch repair
    4. Mismatch repair which can lead to insertion/deletions.

    • Mismatch repair – after proofreading, mismatches identified, improper base excised and replaced w/correct base

      • Adenine methylase recognizes parent strand and adds methyl group to A’s

      • Unmethylated daughter strand recognized by repair enzyme

    Mismatch repair- which can lead to insertion/deletions.

    Important to recognize difference between old strand & new strand:

    If mutated base excised, the wild type is restored, but if the original wild type is excised, the mutant sequence becomes fixed.

    5 post replicational repair sos
    5. Post-replicational repair & SOS which can lead to insertion/deletions.

    Post-replicational repair (aka recombination repair ):

    • Damaged DNA cause Pol III to “stutter” and skip past damaged site

    • Replication restarts downstream and a gap is left

    • Gap is repaired by retrieving sequence from the normal copy and then the subsequent gap is repaired

    Sos response
    SOS response which can lead to insertion/deletions.

    • Severe damage due to alkylating agents or cross-linking agents (UV radiationbest studied) triggers this response

      • Translesional polymerases (POL II, IV, V) can replicate over damaged regions

      • Has very high error rate: 10-2, however allows for survival under extremely bad conditions

    6 double strand break repair
    6. Double strand break repair which can lead to insertion/deletions.

    • Repairs DSBs by reannealing the two DNA segments - protein aligns the broken ends of DNA for rejoining

    • Recombination repair mechanism

      • Homologous recombination repair – damaged DNA replaced by homologous DNA section from sister chromatid

      • Nonhomologous recombination repair – uses non-homologous region for replacement

        • Errors in direct joining may be a cause of translocations