title: Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair.
abstract: 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). 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. 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.
authors.affiliation: Auerback Melanoma Laboratory, Box 0808, Room N431, UCSF Cancer Center, University of California, San Francisco, CA 94143-0808, USA. jcleaver@cc.ucsf.edu
authors.forename: J E
authors.initials: JE
authors.lastname: Cleaver
authors.forename: E
authors.initials: E
authors.lastname: Hefner
authors.forename: R R
authors.initials: RR
authors.lastname: Laposa
authors.forename: D
authors.initials: D
authors.lastname: Karentz
authors.forename: T
authors.initials: T
authors.lastname: Marti
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D003057:Cockayne Syndrome / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics* / Q000528:radiation effects; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes