Studies in the area of gene therapy reported from University of California, Cancer Center
2007 JUN 4 -- A report, "Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair," is newly published data in Neuroscience. "Cockayne syndrome (CS) is a progressive childhood neurodegenerative disorder associated with a DNA repair defect caused by mutations in either of two genes, CSA and CSB. These genes are involved in nucleotide excision repair (NER) of DNA damage from ultraviolet (UV) light, other bulky chemical adducts and reactive oxygen in transcriptionally active genes (transcription-coupled repair, TCR)," investigators in the United States report. "For a long period it has been assumed that the symptoms of CS patients are all due to reduced TCR of endogenous DNA damage in the brain, together with unexplained unique sensitivity of specific neural cells in the cerebellum. Not all the symptoms of CS patients are however easily related to repair deficiencies, so we hypothesize that there are additional pathways relevant to the disease, particularly those that are downstream consequences of a common defect in the E3 ubiquitin ligase associated with the CSA and CSB gene products. We have found that the CSB defect results in altered expression of anti-angiogenic and cell cycle genes and proteins at the level of both gene expression and protein lifetime. We find an over-abundance of p21 due to reduced protein turnover, possibly due to the loss of activity of the CSA/CSB E3 ubiquitylation pathway. Increased levels of p21 can result in growth inhibition, reduced repair from the p21-PCNA interaction, and increased generation of reactive oxygen. Consistent with increased reactive oxygen levels we find that CS-A and -B cells grown under ambient oxygen show increased DNA breakage, as compared with xeroderma pigmentosum cells," wrote J.E. Cleaver and colleagues, University of California, Cancer Center. The researchers concluded: "Thus the complex symptoms of CS may be due to multiple, independent downstream targets of the E3 ubiquitylation system that results in increased DNA damage, reduced transcription coupled repair, and inhibition of cell cycle progression and growth." Cleaver and colleagues published their study in Neuroscience (Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair. Neuroscience, 2007;145(4):1300-8). For additional information, contact J.E. Cleaver, Auerback Melanoma Laboratory, Box 0808, Room N431, UCSF Cancer Center, University of California, San Francisco, CA 94143-0808 USA. The publisher of the journal Neuroscience can be contacted at: Pergamon-Elsevier Science Ltd., the Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, England. Keywords: United States, San Francisco, Biotechnology, Cockayne Syndrome, DNA Damage, DNA Research, Deoxyribonucleic Acid, Gene Therapy, Genetics, Genomics, Neurology, Neuroscience, Proteomics. This article was prepared by Pain & Central Nervous System Week editors from staff and other reports. Copyright 2007, Pain & Central Nervous System Week via NewsRx.com.
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