Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling - PubMed (original) (raw)
Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling
John C Newman et al. Proc Natl Acad Sci U S A. 2006.
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.
Conflict of interest statement
Conflict of interest statement: No conflicts declared.
Figures
Fig. 1.
Many genes that are regulated by CSB are also regulated by HDAC inhibitors (HDACi), inhibitors of DNA methylation, and other factors that disrupt chromatin structure. Shading indicates all such regulated probe sets; colored circles represent significant overlaps between CSB-regulated genes and specific chromatin-related lists in the L2L Microarray Database. Only probe sets on the arrays that represent named genes are shown.
Fig. 2.
Results of analyzing the gene expression patterns of CSB-null and CSB-wt cell lines with the L2L software suite and microarray database. Green and red names of lists denote up- and down-regulation within a particular theme in the database (e.g., all lists of genes up-regulated by Et-743 are red; all lists of genes down-regulated by Et-743 are green). The P values for overlap with genes up- and down-regulated by CSB are indicated in green and red boxes, respectively. (a) Selected Gene Ontology terms found to be significantly overabundant (P < 0.02) among genes regulated by CSB. (b) CSB-regulated genes overlap significantly (P < 0.02) with genes regulated by Et-743, as well as by BRCA1 and -2, PARP, and Elongin A. (c) Summary of themes identified by L2L in the gene expression patterns of CSB-null and CSB-wt cell lines.
Fig. 3.
Treatment with TSA and 3AB partially phenocopy lack of CSB as judged by RT-PCR. Bars are the log2 ratio of gene expression levels in CSB-wt vs. CSB-null cell lines when treated with ethanol alone (white), 1 μM TSA (light gray), or 5 mM 3AB (dark gray). Zero represents no difference in expression between the two cell lines. ∗, P < 0.05 for difference between drug treated and control by Student’s t test of triplicate experiments.
Fig. 4.
CSB-null cells are sensitive to treatment with TSA and 3AB. The number of colonies is normalized to the ethanol control (1.0). ∗, P < 0.05 for the difference between CSB-wt (squares) and CSB-null (circles) by Student’s t test of triplicate experiments.
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