RETRACTED: A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: Implications for a second XPG function

Nouspikel, Thierry; Lalle, Philippe; Leadon, Steven A.; Cooper, Priscilla K.; Clarkson, Stuart G.

doi:10.1073/pnas.94.7.3116

Cited by 147 publications

(130 citation statements)

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“…A limited number of specific mutations in NER genes (XPB, XPD, and XPG) have resulted in patients with a combined XP/ CS phenotype (14)(15)(16)(17)(18). The clinical severity of combined XP/CS probably arises as a result of an inherent link between transcription and NER.…”

mentioning

confidence: 99%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/ CS that cannot be explained by a DNA repair defect.nucleotide excision repair | sirtuins | aging | progeria

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mentioning

confidence: 99%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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“…The clinical features of CS are di cult to reconcile with a repair de®ciency limited to TCR of UV-induced or bulky lesions. Consequently, it has been speculated that subtle defects in the repair of oxidative DNA lesions may contribute to the complex phenotype of a icted individuals Dianov et al, 1997Dianov et al, , 1999Le Page et al, 2000b;Nouspikel et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Global genome repair of 8-oxoG in hamster cells requires a functional CSB gene product

et al. 2002

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Cockayne syndrome (CS) is an autosomal recessive human disease characterized by UV-sensitivity as well as neurological and developmental abnormalities. Two complementation groups have been established, designated CS-A and CS-B. Traditionally, CSA and CSB have been ascribed a function in the transcriptioncoupled repair (TCR) pathway of nucleotide excision repair (NER) that e ciently removes bulky lesions from the transcribed strand of RNA polymerase II transcribed genes. To assess the role of the CSB protein in the repair of the highly mutagenic base lesion 7,8-dihydro-8-oxoguanine (8-oxoG), we have investigated the removal of this lesion using an in vitro incision approach with cell extracts as well as an in vivo approach with a modi®ed protocol of the gene-speci®c repair assay, which allows the measurement of base lesion repair in intragenomic sequences. Our results demonstrate that the integrity of the CSB protein is pivotal for processes leading to incision at the site of 8-oxoG and that the global genome repair (GGR) of this lesion requires a functional CSB gene product in vivo.

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“…Based on this analysis a clear distinction can be made in the nature of the mutations that lead to the XP and XP/CS phenotypes. 56 …”

Section: Xp-g Patients and Their Mutant Allelesmentioning

confidence: 99%

“…All the patients of the XP class expressed at least one full-length allele with a point mutation or frame-shift induced sequence change. In the case of the XP124LO and XP125LO sibling patients, the only stably expressed allele contains an alanine to valine mutation at residue 792, 56,57 immediately adjacent to the highly conserved glutamic acid 791, which is essential for catalysis. Although the A792V allele stably expresses full length XPG protein, this protein has severely reduced nuclease and NER activities.…”

Section: Xp Group G Patients Without Csmentioning

confidence: 99%

“…55 Clarkson et al first reported in 1997 a common mutational pattern that distinguishes XP-G and XP-G/CS patients. 56 Analysis of the mutations in three XP-G/CS patients (XPCS1LV, XPCS2LV and XPCS1RO) revealed that each of them contained mutations that prevented the expression of full-length protein. The patient XPCS1LV expressed only one allele with a stop codon introduced by a single A deletion resulting in a protein of 659 amino acids in length.…”

Section: Patients With Severe Xp and Cs Symptomsmentioning

confidence: 99%

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XPG: Its Products and Biological Roles

Schärer

Molecular Mechanisms of Xeroderma Pigmentosum

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Xeroderma pigmetosum patients of the complementation group G are rare. One group of XP-G patients displays a rather mild and typical XP phenotype. Mutations in these patients interfere with the function of XPG in the nucleotide excision repair, where it has a structural role in the assembly of the preincision complex and a catalytic role in making the incision 3' to the damaged site in DNA. Another set of XP-G patient is much more severely affected, displaying combined symptoms of xeroderma pigmentosum and Cockayne syndrome, referred to as XP/CS complex. Although the molecular basis leading to the XP/CS complex has not yet been fully established, current evidence suggests that these patients suffer from a mild defect in transcription in addition to a repair defect. Here, the history of how the XPG gene was discovered, the biochemical properties of the XPG protein, and the molecular defects found in XP-G patients and mouse models are reviewed.

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RETRACTED: A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G: Implications for a second XPG function

Cited by 147 publications

References 58 publications

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Global genome repair of 8-oxoG in hamster cells requires a functional CSB gene product

XPG: Its Products and Biological Roles

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