TY - JOUR
T1 - Investigations of pyrimidine dimer glycosylases - A paradigm for DNA base excision repair enzymology
AU - Lloyd, R. Stephen
N1 - Funding Information:
I wish to express my genuine thanks to all of the previous and current members of my group that have made these investigations a reality. I have learned from you that the best thing I can do as a mentor is to turn your creativity loose and enjoy with you, your discoveries. I also thank Dr. Amanda McCullough for critically reading this manuscript and Todd Downes for manuscript preparation. This work has been supported by NIH ES04091.
PY - 2005/9/4
Y1 - 2005/9/4
N2 - The most prevalent forms of cancer in humans are the non-melanoma skin cancers, with over a million new cases diagnosed in the United States annually. The portions of the body where these cancers arise are almost exclusively on the most heavily sun-exposed tissues. It is now well established that exposure to ultraviolet light (UV) causes not only damage to DNA that subsequently generates mutations and a transformed phenotype, but also UV-induced immunosuppression. Human cells have only one mechanism to remove the UV-induced dipyrimidine DNA photoproducts: nucleotide excision repair (NER). However, simpler organisms such as bacteria, bacteriophages and some eukaryotic viruses contain up to three distinct mechanisms to initiate the repair of UV-induced dipyrimidine adducts: NER, base excision repair (BER) and photoreversal. This review will focus on the biology and the mechanisms of DNA glycosylase/AP lyases that initiate BER of cis-syn cyclobutane pyrimidine dimers. One of these enzymes, the T4 pyrimidine dimer glycosylase (T4-pdg), formerly known as T4 endonuclease V has served as a model in the study of this entire class of enzymes. It was the first DNA repair enzyme: (1) for which a biologically significant processive nicking activity was demonstrated; (2) to have its active site determined, (3) to have its crystal structure solved, (4) to be shown to carry out nucleotide flipping, and (5) to be used in human clinical trials for disease prevention.
AB - The most prevalent forms of cancer in humans are the non-melanoma skin cancers, with over a million new cases diagnosed in the United States annually. The portions of the body where these cancers arise are almost exclusively on the most heavily sun-exposed tissues. It is now well established that exposure to ultraviolet light (UV) causes not only damage to DNA that subsequently generates mutations and a transformed phenotype, but also UV-induced immunosuppression. Human cells have only one mechanism to remove the UV-induced dipyrimidine DNA photoproducts: nucleotide excision repair (NER). However, simpler organisms such as bacteria, bacteriophages and some eukaryotic viruses contain up to three distinct mechanisms to initiate the repair of UV-induced dipyrimidine adducts: NER, base excision repair (BER) and photoreversal. This review will focus on the biology and the mechanisms of DNA glycosylase/AP lyases that initiate BER of cis-syn cyclobutane pyrimidine dimers. One of these enzymes, the T4 pyrimidine dimer glycosylase (T4-pdg), formerly known as T4 endonuclease V has served as a model in the study of this entire class of enzymes. It was the first DNA repair enzyme: (1) for which a biologically significant processive nicking activity was demonstrated; (2) to have its active site determined, (3) to have its crystal structure solved, (4) to be shown to carry out nucleotide flipping, and (5) to be used in human clinical trials for disease prevention.
KW - DNA base excision repair
KW - DNA-protein covalent intermediates
KW - Nucleotide flipping
KW - Processivity
KW - T4 pyrimidine dimer glycosylase
KW - UV light
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U2 - 10.1016/j.mrfmmm.2005.04.003
DO - 10.1016/j.mrfmmm.2005.04.003
M3 - Review article
C2 - 15923014
AN - SCOPUS:24044523859
SN - 0027-5107
VL - 577
SP - 77
EP - 91
JO - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
JF - Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
IS - 1-2 SPEC. ISS.
ER -