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

Vélez-Cruz, Renier; Zadorin, Anton S.; Coin, Frédéric; Egly, Jean Marc

doi:10.1073/pnas.1213076110

Cited by 30 publications

(29 citation statements)

References 55 publications

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“…This paper provided evidence that CSB and P53 play a reciprocal role in regulating the transcriptional program in response to UV, a concept that has been mechanistically investigated by Fan and colleagues [120, 121]. Also, Velez-Cruz et al [122] recently described a defect in reassembling gene promoters following UV exposure in cells from an XP-D/CS patient, but not in cells from a XP-D patent with pure XP, further supporting the concept of CS as a transcription disorder. Of more physiologic relevance to the internal manifestations of CS, CS cells have a defective response to hypoxia [94].…”

Section: A New Look At An Old Hypothesis: Cs As a Rnapi And Rnapiimentioning

confidence: 74%

Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease

Brooks

2013

DNA Repair

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Cockayne syndrome (CS) is a devastating neurodevelopmental disorder, with growth abnormalities, progeriod features, and sun sensitivity. CS is typically considered to be a DNA repair disorder, since cells from CS patients have a defect in transcription-coupled nucleotide excision repair (TC-NER). However, cells from UV-sensitive syndrome patients also lack TC-NER, but these patients do not suffer from the neurologic and other abnormalities that CS patients do. Also, the neurologic abnormalities that affect CS patients (CS neurologic disease) are qualitatively different from those seen in NER-deficient XP patients. Therefore, the TC-NER defect explains the sun sensitive phenotype common to both CS and UVsS, but cannot explain CS neurologic disease. However, as CS neurologic disease is of much greater clinical significance than the sun sensitivity, there is a pressing need to understand its molecular basis. While there is evidence for defective repair of oxidative DNA damage and mitochondrial abnormalities in CS cells, here I propose that the defects in transcription by both RNA polymerases I and II that have been documented in CS cells provide a better explanation for many of the severe growth and neurodevelopmental defects in CS patients than defective DNA repair. The implications of these ideas for interpreting results from mouse models of CS, and for the development of treatments and therapies for CS patients are discussed.

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Section: A New Look At An Old Hypothesis: Cs As a Rnapi And Rnapiimentioning

confidence: 74%

Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease

Brooks

2013

DNA Repair

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“…We found that both WT XPG and an A792V mutant derived from an XP-G patient form stable complexes with TFIIH, allowing the phosphorylation and transactivation of nuclear receptors, whereas a mutant XPG harboring a C-terminal deletion (derived from an XP-G/CS patient) did not form a complex with TFIIH, resulting in reduced transactivation of nuclear receptors (8). In addition, XP-D/CS, but not XP-D, cells were unable to restart DHFR transcription after UV irradiation, due to Sirt1-mediated heterochromatinization of the promoter (11). Moreover, CSB is known to regulate RNAPI and RNAPII transcription (14,39).…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that XPG forms a stable complex with TFIIH, to facilitate transactivation of nuclear receptors, and that XPG C-terminal truncation (deletion of amino acids 926 to 1186 [⌬926 -1186]) destabilizes the XPG-TFIIH complex, thereby reducing CAK-mediated phosphorylation and transactivation of nuclear receptors (8). In addition, NER factors are involved in the epigenetic regulation of gene expression (9)(10)(11)(12), indicating an important role in gene transcription. RNAPII-mediated transcription can be divided into three steps: initiation, elongation, and termination.…”

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confidence: 99%

Regulation of Transcription Elongation by the XPG-TFIIH Complex Is Implicated in Cockayne Syndrome

Narita

Takedachi

et al. 2015

Molecular and Cellular Biology

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XPG is a causative gene underlying the photosensitive disorder xeroderma pigmentosum group G (XP-G) and is involved in nucleotide excision repair. Here, we show that XPG knockdown represses epidermal growth factor (EGF)-induced FOS transcription at the level of transcription elongation with little effect on EGF signal transduction. XPG interacted with transcription elongation factors in concert with TFIIH, suggesting that the XPG-TFIIH complex serves as a transcription elongation factor. The XPG-TFIIH complex was recruited to promoter and coding regions of both EGF-induced (FOS) and housekeeping (EEF1A1) genes. Further, EGF-induced recruitment of RNA polymerase II and TFIIH to FOS was reduced by XPG knockdown. Importantly, EGF-induced FOS transcription was markedly lower in XP-G/Cockayne syndrome (CS) cells expressing truncated XPG than in control cells expressing wild-type (WT) XPG, with less significant decreases in XP-G cells with XPG nuclease domain mutations. In corroboration of this finding, both WT XPG and a missense XPG mutant from an XP-G patient were recruited to FOS upon EGF stimulation, but an XPG mutant mimicking a C-terminal truncation from an XP-G/CS patient was not. These results suggest that the XPG-TFIIH complex is involved in transcription elongation and that defects in this association may partly account for Cockayne syndrome in XP-G/CS patients.

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“…These XPB and XPD mutations may prevent CAK module dissociation that is required for NER or could block normal function of other DNA repair factors to cause delayed transcriptional resumption (i.e. after DNA damage) commonly seen in XP/CS patients …”

Section: Pathologies Associated With Tfiih Functionmentioning

confidence: 99%

The essential and multifunctional TFIIH complex

Rimel

Taatjes²

2018

Protein Science

108

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TFIIH is a 10‐subunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoter‐proximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function.

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

Cited by 30 publications

References 55 publications

Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease

Blinded by the UV light: How the focus on transcription-coupled NER has distracted from understanding the mechanisms of Cockayne syndrome neurologic disease

Regulation of Transcription Elongation by the XPG-TFIIH Complex Is Implicated in Cockayne Syndrome

The essential and multifunctional TFIIH complex

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