The 8,5′-cyclopurine-2′-deoxynucleosides: Candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair

It is a commonly held view that oxidatively induced DNA lesions are repaired by the base excision repair (BER) pathway, whereas DNA lesions induced by UV light and other “bulky” chemical adducts are repaired by the nucleotide excision repair (NER) pathway. While this distinction is generally accurat...

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Bibliographic Details
Published in:DNA repair 2008-07, Vol.7 (7), p.1168-1179
Main Author: Brooks, P.J.
Format: Article
Language:English
Subjects:
Bacteriology
Biological and medical sciences
Deoxyribonucleosides - chemistry
Deoxyribonucleosides - metabolism
Dermatology
DNA Adducts - metabolism
DNA Damage
DNA Repair
Fundamental and applied biological sciences. Psychology
Growth, nutrition, cell differenciation
Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue
Humans
Medical sciences
Microbiology
Molecular and cellular biology
Molecular genetics
Mutagenesis. Repair
Neurodegeneration
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - metabolism
Oxidative DNA damage
Oxidative stress
Reactive oxygen species
RNA polymerase
Transcription, Genetic
Xeroderma pigmentosum
Xeroderma Pigmentosum - genetics
Xeroderma Pigmentosum - metabolism
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Summary:It is a commonly held view that oxidatively induced DNA lesions are repaired by the base excision repair (BER) pathway, whereas DNA lesions induced by UV light and other “bulky” chemical adducts are repaired by the nucleotide excision repair (NER) pathway. While this distinction is generally accurate, the 8,5′-cyclopurine deoxynucleosides represent an important exception, in that they are formed in DNA by the hydroxyl radical, but are specifically repaired by NER, not by BER. They are also strong blocks to nucleases and polymerases, including RNA polymerase II in human cells. In this review, I will discuss the evidence that these lesions are in part responsible for the neurodegeneration that occurs in some XP patients, and what additional evidence would be necessary to prove such a role. I will also consider other DNA lesions that might be involved in XP neurologic disease. Finally, I will also discuss how our recent studies of these lesions have generated novel insights into the process of transcriptional mutagenesis in human cells, as well as the value of studying these lesions not only for a better understanding of NER but also for other aspects of human health and disease.
ISSN:1568-7864
1568-7856
DOI:10.1016/j.dnarep.2008.03.016