1. Prof. Avram Gold Rosenau 157 966-7304 golda@email.unc.edu
DNA Adducts, Mutations, DNA Damage, DNA Repair, Mechanisms of Mutagenesis
Prof. Avram Gold
Rosenau 157

2. RELATION BETWEEN DNA DAMAGE AND MUTATION
DNA +activated compound
lesion
processing/repair
no effect
mutation
RELATION BETWEEN DNA DAMAGE AND MUTATION

3. glycosidic bond to base
A, Ade
G, Gua
C, Cyt
T, Thy
2’-deoxyribose
glycosidic bond to base
phosphate

4. PAIRING SCHEME OF DNA BASES AND DIRECTIONALITY OF DNA STRANDS
and also appropriate nomenclature
phosphodiester {
bond 3’ 5 5’
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

5. Ribbon representation of DNA
major groove
minor groove

6. Sites of electrophilic attack on purines.
Adducts at N1 and N3 are less common.
Order of reactivity:Gua  Ade  C  T
Sites of electrophilic attack on purines.
Nomenclature convention: sites are superscripted when not part of the ring structure. Thus, O6, N2 and N6, but N3 and N7.

7. 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.

8. http://highered. mcgraw-hill

9. EXCISION REPAIR PATHWAY

11. 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:
keto form (normal)
enol form = H
Keto-enol tautomerization of guanine

12. CLASSES OF POINT MUTATIONS
FIXING A MUTATION
One round of replication on mismatched strands “fixes” the mutation. *
G·T ® G·T + A·T *
CLASSES OF POINT MUTATIONS
Point mutation, transition
pyrimidinepyrimidine
purinepurine
G·C ® A·T
A·T ® G·C
Point mutation, transversion
pyrimidinepurine
purinepyrimidine
G·C ® C·G, T·A ® A·T, G·C ® T·A
nonsense mutation occurs when a termination codon is generated
missense mutation occurs when a different amino acid is coded

13. ATC GCT TAA TTC GCA CCT TAC TA
FRAME SHIFT MUTATIONS
-1 frameshift
ATC GCT TAA TTC GCA CCT TAC TA
delete G
wild type
ATC GGC TTA ATT CGC ACC TTA CTA
insert G
+1 frameshift
ATC GGG CTT AAT TCG CAC CTT ACT A

14. CATEGORIES OF DAMAGE 1. Bulky covalent adducts.
2. Sterically benign covalent adducts (do not distort DNA).
3. Alteration of nucleobase structure without formation of covalent adducts.

15. METABOLIC SCHEME OF BENZO[a]PYRENE (BP, B[a]P)
ultimate active metabolite BPDE
proximate metabolites
METABOLIC SCHEME OF BENZO[a]PYRENE
(BP, B[a]P)
7,8-Quinone
7,8-catechol