Transcriptional profiles of unirradiated or UV-irradiated human cells expressing either the cancer-prone XPB/CS allele or the noncancer-prone XPB/TTD allele

Costa, Ana Rita; Riou, Lydia; Paquola, Apuã C.M.; Menck, Carlos Frederico Martins; Sarasin, Alain

doi:10.1038/sj.onc.1208288

Cited by 33 publications

(23 citation statements)

References 36 publications

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“…At least two scenarios might explain these puzzling overlaps: (i) damage-regulated genes might be coincidentally regulated by other stress-response pathways in CSB-null cells, or (ii) CSB-null cells might attempt to generate a proper transcriptional response to DNA damage but fail. Previous studies of CSB and XPB͞CS cells found that their transcriptional response to DNA damage was deficient (17) or delayed (21), consistent with our evidence for a chromatin remodeling defect. Moreover, the sole strong correlation between CSB-regulated genes and the DNA damage response, a striking overlap between CSB and the anticancer drug Ecteinascidin 743 (Et-743; see Fig.…”

supporting

confidence: 80%

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Newman

Bailey

Weiner³

2006

Proc. Natl. Acad. Sci. U.S.A.

137

129

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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 SWI͞SNF-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 growthsuppressive, inflammatory, and proapoptotic pathways.DNA repair ͉ L2L ͉ microarray ͉ transcription C ockayne syndrome (CS) is a devastating inherited disease characterized by severe postnatal growth failure and progressive neurological dysfunction, along with a variety of symptoms reminiscent of aging, including retinal degeneration, sensorineural hearing loss, cataracts, and loss of subcutaneous fat (1). The nature of the molecular defect that causes CS remains elusive, although CS has been intensively studied for many years, and much is known about the cellular functions of the five genes responsible for the disease. Most cases of CS are caused by defects in two genes: CS groups A (CSA) and B (CSB). The CSB protein is a SWI͞SNF-like DNA-dependent ATPase (2-4) that can wind DNA (5) and remodel chromatin in vitro (6). CSB is required for translocation of the CSA protein to the nuclear matrix after DNA damage (7). Rare alleles of three xeroderma pigmentosum (XP) genes (XPB, XPD, and XPG) are responsible for the remaining cases of CS; these patients usually lack the severe predisposition to skin cancer typical of XP (8). CS genes have been implicated, alone or in various combinations, in transcription-coupled repair (TCR) of UV-induced DNA lesions (9, 10), repair of oxidative DNA damage (11), transcription initiation by RNA polymerase I (pol I; refs. 12 and 13) and RNA polymerase II (pol II; ref. 14), elongation by pol II (15, 16), transcription of induced genes (17), protein ubiquitination (18), and metaphase chromosome condensation (19).To understand how CSB defects cause CS, we characterized the array of genes regulated by CSB. Previous expression array studies, although encouraging, had not been conclusive (20) or had focused on the role of CS genes in the transcriptional response to oxidative (17) or ultraviolet (21) DNA damage. Our hope was to work backwards from effect to cause, deducing the biochemical functions of CSB from genes it...

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supporting

confidence: 80%

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Newman

Bailey

Weiner³

2006

Proc. Natl. Acad. Sci. U.S.A.

137

129

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“…Many genes are known to be up-or down-regulated following exposure to DNA damaging agents and there are several reports on expression profile changes following UV-irradiation of human cells [33,[37][38][39][40]. Likewise we observed many genes clearly up-or down-regulated following UV-C-irradiation of human fibroblasts.…”

Section: Discussionsupporting

confidence: 59%

“…The first approach entailed comparing the transcriptional profiles of cells in which the phenotype has been corrected by introduction of the wild-type XPD gene. A similar approach was used by Costa et al with XP-B cells [33]. They used a cell line from a patient with the combined features of XP and CS as recipient for XPB cDNA containing either the same mutation as found in the recipient cell or a mutation found in a TTD patient.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional changes in trichothiodystrophy cells

et al. 2008

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Mutations in three of the genes encoding the XPB, XPD and TTDA components of transcription factor TFIIH can result in the clinical phenotype of trichothiodystrophy (TTD). Different mutations in XPB and XPD can instead cause xeroderma pigmentosum (XP). The completely different features of these disorders have been attributed to TTD being a transcription syndrome. In order to detect transcriptional differences between TTD and XP cells from the XP-D complementation group, we have compared gene expression profiles in cultured fibroblasts from normal, XP and TTD donors. Although we detected transcriptional differences between individual cell strains, using an algorithm of moderate stringency, we did not identify any genes whose epression was reproducibly different in proliferating fibroblasts from each type of donor.Following UV-irradiation, many genes were up-and down-regulated in all three cell types. The micro-array analysis indicated some apparent differences between the different donor types, but on more detailed inspection, these turned out to be false positives. We conclude that there are minimal differences in gene expression in proliferating fibroblasts from TTD, XP-D and normal donors.Dear Errol I enclose a manuscript entitled "Transcriptional changes in trichothiodystrophy cells" that we would like to be considered for publication in DNAR. This paper reports on a very careful study that we have carried out, using micro-arrays, to look for specific transcriptional differences between TTD fibroblasts and XP-D or normal fibroblasts, both in unirradiated and irradiated cells. We were not able to detect any differences that could be attributed to a TTD-specific genotype. En route our study highlights a number of potential pitfalls that need to be avoided when using such an approach. In particular using a single defective cell line and its corrected derivative might generate data that can be easily misinterpreted.We hope that the results in this paper will be of interest to readers of DNAR.Best regards. strains, using an algorithm of moderate stringency, we did not identify any genes whose expression was reproducibly different in proliferating fibroblasts from each type of donor. Following UV-irradiation, many genes were up-and down-regulated in all three cell types. The micro-array analysis indicated some apparent differences between the different donor types, but on more detailed inspection, these turned out to be false positives. We conclude that there are minimal differences in gene expression in proliferating fibroblasts from TTD, XP-D and normal donors.3

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“…Both UV and ionizing radiation increase the transcription of hundreds of genes, including genes directly involved in NER such as XPC, DDB2, PCNA, and Gadd45A (Rieger and Chu 2004;Boerma et al 2005;da Costa et al 2005). However, it has also been reported that cellular protein synthesis is markedly inhibited after UV irradiation (Deng et al 2002;Wu et al 2002).…”

mentioning

confidence: 97%

Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes

Powley¹,

Kondrashov²,

Young³

et al. 2009

Genes Dev.

134

154

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UVB-induced lesions in mammalian cellular DNA can, through the process of mutagenesis, lead to carcinogenesis. However, eukaryotic cells have evolved complex mechanisms of genomic surveillance and DNA damage repair to counteract the effects of UVB radiation. We show that following UVB DNA damage, there is an overall inhibition of protein synthesis and translational reprogramming. This reprogramming allows selective synthesis of DDR proteins, such as ERCC1, ERCC5, DDB1, XPA, XPD, and OGG1 and relies on upstream ORFs in the 59 untranslated region of these mRNAs. Experiments with DNA-PKcs-deficient cell lines and a specific DNA-PKcs inhibitor demonstrate that both the general repression of mRNA translation and the preferential translation of specific mRNAs depend on DNA-PKcs activity, and therefore our data establish a link between a key DNA damage signaling component and protein synthesis.[Keywords: DNA damage; translation; upstream ORF] Supplemental material is available at http://www.genesdev.org.

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Transcriptional profiles of unirradiated or UV-irradiated human cells expressing either the cancer-prone XPB/CS allele or the noncancer-prone XPB/TTD allele

Cited by 33 publications

References 36 publications

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

Transcriptional changes in trichothiodystrophy cells

Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes

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