DNA Adducts, Mutations, DNA Damage, Mechanisms of Mutagenesis

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DNA Adducts, Mutations, DNA Damage, Mechanisms of
Mutagenesis

• Prof. Avram Gold
• Rosenau 157
• 966-7304
• golda_at_email.unc.edu

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Genetic Toxicology
Reading material Casarett and Doull Chapter
9, Timbrell, Chapter 6, pp. 259-279
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Schematic of association of strands in DNA double
helix
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PAIRING SCHEME OF DNA BASES AND DIRECTIONALITY OF
DNA STRANDS and also appropriate nomenclature
nucleobases guanine (Gua, G) adenine (Ade,
A) cytosine (Cyt, C) thymine (Thy,
T) nucleosides (deoxy-) guanosine (dGuo,
dG) adenosine (dAdo, dA) cytidine (dCyd,
dC) thymidine (dThyd, dT) nucleotides
(deoxy-) guanylic acid adenylic acid cytidylic
acid thymidylic acid
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Ribbon representation of DNA
minor groove
major groove
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FUNCTIONS OF DNA

• REPLICATION
• 1. DNA stores and passes on genetic information
  which consists of codes for amino acids and their
  sequence in proteins. The information is coded
  by the arrangement of nucleobases in groups of
  three, called triplets or codons, where each
  codon represents an amino acid.
• TRANSCRIPTION
• 2. DNA is also used for translating genetic
  information into the proteins necessary for
  organisms to grow and survive.

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Link to animation http//highered.mcgraw-hill.com
/sites/0072437316/student_view0/chapter14/animatio
ns.html
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Methylation at O6 of dGuo and O4 of dThyd results
in instructional lesions that lead directly to
mis-pairing of bases and a base pair substitution
mutation when the strand bearing the wrong
partner is a template for replication
H
Keto-enol tautomerization of guanine
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FIXING A MUTATION
One round of replication on mismatched strands
fixes the mutation.


GT GT AT
CLASSES OF POINT MUTATIONS
Point mutation, transition pyrimidine?pyrimidine p
urine?purine
GC AT AT GC
Point mutation, transversion pyrimidine?purine pur
ine?pyrimidine
GC CG, TA AT, GC TA
nonsense mutation occurs when a termination codon
is generated missense mutation occurs when a
different amino acid is coded
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FRAME SHIFT MUTATIONS
ATC GCT TAA TTC GCA CCT TAC TA
-1 frameshift
delete G
ATC GGC TTA ATT CGC ACC TTA CTA
wild type
insert G
ATC GGG CTT AAT TCG CAC CTT ACT A
1 frameshift
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Mechanism for frameshift mutations
G-p
3'-G-p-G-p-G-p-G-p-G-p-G-5' 3'-G-p-G-p
G-p-G-p-G-p-G-5' 5'-C-p-C p-C-OH 5'-C-p-C-p-C-O
H
p-C
insertion
deletion
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CATEGORIES OF DAMAGE
1. Bulky covalent adducts causing distortion of
the helix. 2. Sterically benign covalent adducts
(do not distort DNA) that may be promutagenic. 3.
Alteration of nucleobase structure without
formation of covalent adducts.
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