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and thus depending on the agent used to damage the
DNA and the chemistry of the adduct formed, reduction
in DDB activity may not necessarily impact cellular
sensitivity to the agent. In the context of cisplatin, DDB
is only required for repair of the 1,2 d(GpG) lesion and
repair of the 1,3 (GpXpG) lesion occurs independently
of DDB. Therefore, from the perspective of DNA
damage recognition, targeting these two proteins for
therapeutic benefit is less likely to be successful. Inter-
estingly, both DDB2 and XPC are involved in the ubiqui-
tination pathway and play roles, though not completely
defined, in DNA damage signaling. In this context, tar-
geting these two proteins may prove useful, a point
that will only be supported by further experimentation.
6. Chen X, Zhang Y, Douglas L, Zhou P. UV-damaged DNA-
binding proteins are targets of CUL-4A-mediated ubiquitina-
tion and degradation. J Biol Chem 2001;
82.
7. Nag A, Bondar T, Shiv S, Raychaudhuri P. The xeroderma
pigmentosum group E gene product DDB2 is a specific target of
cullin 4A in mammalian cells. Mol Cell Biol 2001;
276
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8. Sugasawa K, Okamoto T, Shimizu Y, Masutani C, Iwai S,
Hanaoka F. A multistep damage recognition mechanism for
global genomic nucleotide
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21
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9. Dip R, Camenisch U, Naegeli H. Mechanisms of DNA damage
recognition and strand discrimination in human nucleotide
excision repair. DNA Repair 2004;
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15
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10. Laine JP, Mocquet V, Egly JM. TFIIH enzymatic activities in
transcription and nucleotide excision repair. DNA Repair Pt A
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3
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11. Staresincic L, Fagbemi AF, Enzlin JH, et al. Coordination of dual
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12. Moser J, Kool H, Giakzidis I, Caldecott K, Mullenders LH,
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nucleotide excision repair requires XRCC1 and DNA ligase III
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CONCLUSIONS
The NER pathway involves a complex series of reac-
tions and interactions that lead to the effective removal
of damage from DNA and is crucial in maintaining
genome integrity and stability. The role of NER in
removing cisplatin chemotherapy-induced DNA
damage and the demonstrated mechanism of resistance
in multiple cancers involving increased repair presents
the opportunity for intervention. Realization of this
potential to sensitize cancers to cisplatin and reverse
resistance of those cancers that develop an insensitivity
to this agent will require the development of specific
agents capable of targeting the NER pathway. The possi-
bility exists that the success of platinum therapy in the
treatment of testicular cancer can be replicated in lung
and ovarian cancers where the lack of response to plat-
inum therapy is a major determinant of the dismal
survival statistics associated with those diseases. Such
a finding would be a watershed event that could
dramatically alter treatments of human cancer.
23.
13. Mocquet V, Laine JP, Riedl T, Yajin Z, Lee MY, Egly JM.
Sequential recruitment of the repair factors during NER: the
role of XPG in initiating the resynthesis step. EMBO J
2008;
(2):311
27
e
67.
14. Nouspikel T. Nucleotide excision repair and neurological
diseases. DNA Repair (Amst) 2008;
27
(1):155
e
67.
15. Aboussekhra A, Biggerstaff M, Shivji MK, et al. Mammalian
DNA nucleotide excision repair reconstituted with purified
protein components. Cell 1995;
7
(7):1155
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68.
16. Laine JP, Egly JM. When transcription and repair meet:
a complex system. Trends Genet 2006;
(6):859
80
e
6.
17. Ueda T, Compe E, Catez P, Kraemer KH, Egly JM. Both XPD
alleles contribute to the phenotype of compound heterozygote
xeroderma pigmentosum patients.
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22
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J Exp Med 2009;
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206
46.
18. Nardo T, Oneda R, Spivak G, et al. A UV-sensitive syndrome
patient with a specific CSA mutation reveals separable roles for
CSA in response to UV and oxidative DNA damage. Proc Natl
Acad Sci USA 2009;
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19. Horibata K, Iwamoto Y, Kuraoka I, et al. Complete absence of
Cockayne syndrome group B gene product gives rise to UV-
sensitive syndrome but not Cockayne syndrome. Proc Natl Acad
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20.
Itoh T, Ono T, Yamaizumi M. A new UV-sensitive syndrome not
belonging to any complementation groups of xeroderma pig-
mentosum or Cockayne syndrome: siblings showing biochem-
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