title: Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling.
abstract: Cockayne syndrome (CS) is an inherited neurodevelopmental disorder with progeroid features. Although the genes responsible for CS have been implicated in a variety of DNA repair- and transcription-related pathways, the nature of the molecular defect in CS remains mysterious. Using expression microarrays and a unique method for comparative expression analysis called L2L, we sought to define this defect in cells lacking a functional CS group B (CSB) protein, the SWI/SNF-like ATPase responsible for most cases of CS. Remarkably, many of the genes regulated by CSB are also affected by inhibitors of histone deacetylase and DNA methylation, as well as by defects in poly(ADP-ribose)-polymerase function and RNA polymerase II elongation. Moreover, consistent with these microarray expression data, CSB-null cells are sensitive to inhibitors of histone deacetylase or poly(ADP-ribose)-polymerase. Our data indicate a general role for CSB protein in maintenance and remodeling of chromatin structure and suggest that CS is a disease of transcriptional deregulation caused by misexpression of growth-suppressive, inflammatory, and proapoptotic pathways.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA 98195-7350, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Newman
authors.forename: Arnold D
authors.initials: AD
authors.lastname: Bailey
authors.forename: Alan M
authors.initials: AM
authors.lastname: Weiner
mesh_terms: D002460:Cell Line; D002470:Cell Survival; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology*; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D000075065:Elongin; D018628:Gene Dosage; D015870:Gene Expression; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D004149:Dioxoles; D000075065:Elongin; D056572:Histone Deacetylase Inhibitors; D007546:Isoquinolines; D000075223:Poly-ADP-Ribose Binding Proteins; D044005:Tetrahydroisoquinolines; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011065:Poly(ADP-ribose) Polymerases; D019098:Telomerase; D006655:Histone Deacetylases; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes; D000077606:Trabectedin