DNA mutation

DNA mutation：type of mutations、Type of leisions、Source of Damages、DNA repair.

DNA mutation

• type of mutations
  • single base/point mutation
    • Reversion
      • True reversion
        • second mutation restores DNA sequence
      • Suppression
        • Intragenic
          • insersion followed by deletion
        • Intergenic
          • double mutant between interacting proteins
          • tRNA suppression
            • mutation on tRNA gene
              • stop nonsence mutation
    • substitusion
      • fixation
        • after DNA replications
      • chemically
        • transition
          • purine to purine, pyrimidine to pyrimidine
            • 4 possibillities
        • transversion
          • pyrimidine to purine, purine to pyrimidine
            • 8 possibillities
      • codon sense
        • silent
          • same aminoacids' degeneracy codon
        • missense
          • change 1 amino acids
          • neutral
            • a similar propertie's amino acid
        • nonsense
          • stop codon
    • addition/deletion
      • codon sence
        • usually frameshift
    • other consequences
      • altered splicing partern
        • lose exon/ adds intron: frame-shift/ trancate results
  • genes
    • duplication
  • chromosomes
    • inversion
    • deletion
    • translocation
  • genomes
    • euploidy
    • aneuploidy
• Type of leisions
  • mismatch
    • arrised from keto-enol tautomers escape proof reading+mismatch repair
  • loopingout
    • replication
      • parental/ template strand loops out
        • results in deletion of the complementary strand
      • Most readily occurs in a run of identical bases
  • noncoding
    • spontaneously debase
      • depurination
      • depyridination
      • produce abasic noncoding site: 100000 per cells per day
  • Bulky
    • UV Cyclobutane pyrimidine dimers (thymine dimers) and 6-4 photoproducts bulky leisions
    • can block DNA replication and transcription
  • strand breaks
    • ionizing radiation: nonreversible deletion result in
• Source of Damages
  • Spontaneous
    • errors during Replication
      • Mismatch
        • arrised from keto-enol tautomers escape proof reading+mismatch repair
      • loopingout
        • parental/ template strand loops out
          • results in deletion of the complementary strand
        • Most readily occurs in a run of identical bases
    • spontaneous self modification
      • deamination
        • cytosine deamination
          • C to U
            • transistion
          • increased by nitrous acid
        • 5-mec deamination
          • 5-mec to T
      • debase
        • depurination
        • depyridination
        • produce abasic noncoding site: 100000 per cells per day
    • cellular damaging agents
      • Reactive oxygen species
        • superoxide, hydroxyl radical, peroxide
      • G to 8-hydroxyguanine
        • 8-hydroxyguanine pair with C/A
          • cause transversion
      • S-adenosylmethionine methylates G, T, A
        • O6-methylguanine
          • pair with C/T
            • cause GC to AT transition
  • Induced
    • Physical
      • ionizing radiation
        • X-rays, γ-rays
          • Direct — interaction of high energy photons with DNA
          • Indirect — interaction of e- and ROS (formed by radiolysis of water) with DNA
          • cause strand breaks
            • single
            • double
            • leads to nonreversible deletion
      • non-ionizing radiation
        • UV
          • Cyclobutane pyrimidine dimers (thymine dimers) and 6-4 photoproducts
            • bulky leisions
    • Chemical
      • Base analogues
        • Keto (normal) tautomer of 5-BrU pairs with A
        • Enol tautomer pairs with G
        • Causes TA to CG and CG to TA transitions
      • Base modifying agents
        • acid promotes C deamination. Resulting U pairs with A.
          • accelerated deamination processes
        • Hydroxylamine produces hydroxylaminocytosine — pairs with A
        • Alkylating agents
          • Electrophilic compounds that attack nucleophilic centres on DNA
          • •N-Methyl-N-nitroso-N’-nitroguanidine (MNNG)
          • •Methyl methanesulphonate (MMS)
          • •Ethyl methanesulphonate (EMS)
          • •Nitrosamines
            • Dietary nitrites can form nitrosamines in stomach
        • Arylating agents
          • resulting NON-informational or blocking lesions stop DNA polymerase recognation
          • Error-prone repair, lesion bypass mechanisms may then operate
          • Bi-functional alkylating agents can cross-link strands e.g. mitomycin C (from Strep. Sp)
        • Arylating agents
          • ex.PAH
            • • Non-informational, non-coding BULKY ADDUCTS (cf thymine dimers) block replication and transcription • Activated to diol epoxide by liver cytochrome P-450s
          • Aflatoxin B1
            • Potent liver carcinogen found in peanut fungus
          • ptaquiloside
            • carcinogen in bracken fern
              • •Reacts with adenine
              • •Causes strand breaks
        • Intercalating agents
          • ethidium bromide, proflavin and acridine orange
          • Cause frameshift mutations: additions or deletions depending on whether they intercalate into the template or newly synthesised DNA strand.
• DNA repair
  • Direct repair
    • DNA ligase
      • repair "Nicks"
        • form phosphodiester bond between approximated 3'OH and 5' OPO32-
    • Alkyltransferase
      • deakylates
        • O4-alkylthymine
        • O6-methylguanine
      • Suicide inactivation
    • Photoreactivation
      • Photolyase (flavoprotein) repair UV leision using light as energy source
  • Excision repair
    • Methyl-directed Mismatch Repair (MMR)
      • mismatch targeting
      • require methylated DNA around to direct repair in e. coli
        • but not in human
      • excise by mut H
      • synthesize by DNApol III
    • Nucleotide Excision Repair (NER)
      • bulky leision targeting
      • excise and synthesized by DNApol I
    • Base Excision Repair (BER)
      • specific altered sites recognized by different glycosylases
      • exice by AP endonuclease
  • Strand break repair
    • Single-strand break repair
    • Double-strand break repair
      • Non-Homologous End Joining (NHEJ)
      • Homologous Recombination (HRR)
  • Ecoli SOS