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FIGURE 6.1 Nucleotide excision repair pathway. (1) DNA
damage is initially recognized and verified via protein-DNA
interactions sensing the distortion and chemical modification
of the DNA duplex. (2) Nuclease binding is followed by
ERCC1/XPF catalyzed incision. (3) DNA synthesis precedes
XPG catalyzed 3' incision. DNA synthesis continues to
generate a nick which is ultimately ligated to complete repair.
complementation groups with XPA often being the most
severe, while XPE is the least severe. This is interesting
in that both are involved in DNA damage recognition
and verification though XPE (DDB) appears to be
required for only a subset of lesions. 15 Repair of those
DNA adducts that result in minimal distortion of the
duplex DNA structure is enhanced by XPE while the
more distorting lesions are less affected by XPE defi-
ciency. In addition to the differences in sensitivity
between complementation groups, there are species-
specific differences within a single complementation
group. This is highlighted in the case of XPF, where
murine XPF-null cells are viable and result in a dramatic
increase in UV sensitivity while human XPF-null cells
are not found in nature and XPF individuals retain
some protein expression and activity.
Cockayne syndrome is often described as a disease of
transcription. 16 Individuals with CS are not predisposed
to cancer development but do present with develop-
mental and neurological deficits. The two CS complemen-
tation groups, CSA and CSB, encode proteins required for
the TC-NER while GG-NER is not affected. Interestingly,
mutations in XPC and DDB display the opposite pheno-
type, defective GG-NER while retaining fully functional
TC-NER. A complex phenotype with defects in both
DNA repair and transcription, UV-sensitivity, cancer
predisposition, and developmental and neurological
abnormalities are seen with certain mutations in the two
helicase subunits of TFIIH, XPB, and XPD as well as
XPG. This combined XP/CS phenotype adds to the
complexity of the interactions and effects on both tran-
scription as well as DNA repair. 17 Similar to CS, UV sensi-
tive syndrome (UV S S) is a rare disease characterized by
sensitivity to UV light and the inability to carry out
TC-NER. 18 e 20 UV S S, however, is not characterized by
any developmental or neurological abnormalities. This
has led to the possibility that CSA- and CBS-dependent
TC-NER of other types of lesions including oxidative
lesions may be responsible for the neurological and
developmental abnormalities in CS patients.
TTD is another rare autosomal recessive disorder
mapped to specific mutations in the XPB, XPD, and p8
subunits of TFIIH. 21,22 This disease is characterized by
brittle hair and nails as a result of reduced sulfur con-
taining matrix proteins that provide the resilience for
hair and nails. Interestingly, there is minimal UV sensi-
tivity and skin cancer rarely is observed in these individ-
uals. However, in vitro analysis of cell lines generated
from patients with XPB and XPD mutations do display
slight UV sensitivity consistent with a DNA repair
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