Nucleic Acids in Chemistry and Biology

dimer lesion. First, in the case of the lesion T<>T, pol I is able to bypass the dimer and incorporates
adenines opposite the lesion with less than 95% efficiency (Figure 8.44). This explains why T<>T appears
to be inherently non-mutagenic. Second, adenines are also incorporated when the dimer is T<>U, and this
strongly supports the idea that T<>C and C<>T photodimers cause G → A transition mutations. This can
be a result either of deamination of the cytidine residue to give a deoxyuridine photoproduct prior to replication,
deamination bypass, or of mispairing of the T<>C dimer with the 5,6-saturated cytosine moiety in its imino
tautomeric form, tautomer bypass(Section 2.1.2). Third, when T<>T dimers are incorporated into oligo(dl)
tracts, specifically at positions -2 and -3 from the 5
-end of the Tntract, both -1 and -2 deletions are observed.
Studies of this nature can be expected to uncover the role of bipyrimidine (6-4) photoproducts and other
DNA lesions in due course.^114
The main DNA repair processes in humans are: direct repair (DR), base excision repair (BER), nucleotide
excision repair (NER), mismatch repair (MMR), along with homologous recombination (HR) and non-homol-
ogous end-joining (NHEJ). Studies on human repair systems are advancing rapidly, especially into UV dam-
age. Recent studies have shown that human DNA polymerase (Pol ) modulates susceptibility to skin cancer
by promoting DNA synthesis past sunlight-induced cyclobutane pyrimidine dimers that escape nucleotide
excision repair (NER). Pol bypasses a dimer with low fidelity and with higher error rates at the 3
-thymine
than at the 5
-thymine and UV-induced mutagenesis is higher at the 3
-base of dipyrimidine sequences. Thus,
in normal people and particularly in individuals with NER-defective Xeroderma pigmentosumwho accumu-
late dimers, errors made by Pol during dimer bypass may contribute to mutagenesis and skin cancer.^115
These human repair systems are key players in maintaining our genomic integrity while defects in many
of these pathways have been linked to particular human hereditary syndromes. Our growing understand-
ing of these processes is a prime area for the interplay of the chemistry and biology of nucleic acids and
will continue to enhance our ability to identify and resist environmental hazards.

Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 333

5' T<>X

p

template

primer

Pol I

dNTPs

fast

5' T<>X 3'

p

dNMP

proofreading

Pol I

dNTPs

slow

template

arrest product

5' T<>X 3' template

N arrest product

5' T<>X 3' template

arrest product

dAMP

proofreading

Pol I

dATP

slow

A–N

5' T<>X 3' template

A–N bypass

Pol I

dNTPs

fast

p

p

p

3'

Figure 8.44 Bypass mutagenesis illustrated by the scheme employed to investigate the kinetics and mutagenic
consequences of the bypass of DNA cyclobutane photoproducts by polymerase I in vitro