Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease

Wang, Yuming; Chakravarty, Probir; Ranes, Michael; Kelly, Gavin; Brooks, Philip J.; Neilan, Edward G.; Stewart, Aengus; Schiavo, Giampietro; Svejstrup, Jesper Q.

doi:10.1073/pnas.1412569111

Cited by 91 publications

(101 citation statements)

References 36 publications

(33 reference statements)

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“…8E). This observation may reflect an overall impact of CSB transient re-expression on nascent RNA synthesis and is consistent with the role of CSB as a chromatin remodeler in transcription in numerous genes (45,46). VCP/p97 inhibition increased RRS even in the absence of CSB induction (Fig.…”

Section: Volume 291 • Number 14 • April 1 2016supporting

confidence: 84%

Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin

Zhu

Wani

et al. 2016

Journal of Biological Chemistry

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Cockayne syndrome group A and B (CSB) proteins act in transcription-coupled repair, a subpathway of nucleotide excision repair. Here we demonstrate that valosin-containing protein (VCP)/p97 segregase functions in ultraviolet radiation (UVR)-induced ubiquitin-mediated CSB degradation. We show that VCP/p97 inhibition and siRNA-mediated ablation of VCP/p97 and its cofactors UFD1 and UBXD7 impair CSB degradation. VCP/p97 inhibition also results in the accumulation of CSB in chromatin. Moreover, VCP/p97 interacts with both native and ubiquitin-conjugated forms of CSB. The localized cellular UVR exposures lead to VCP/p97 accumulation at DNA damage spots, forming distinct UVR-induced foci. However, manifestation of VCP/p97 foci is independent of CSB and UBXD7. Furthermore, VCP/p97 and UBXD7 associate with the Cockayne syndrome group A-DDB1-Cul4A complex, an E3 ligase responsible for CSB ubiquitination. Compromising proteasome and VCP/p97 function allows accumulation of both native and ubiquitinated CSB and results in an increase of UBXD7, proteasomal RPN2, and Sug1 in the chromatin compartment. Surprisingly, both biochemical inhibition and genetic defect of VCP/p97 enhance the recovery of RNA synthesis following UVR, whereas both VCP/p97 and proteasome inhibitions decrease cell viability. Our findings reveal a new role of VCP/p97 segregase in the timely processing of ubiquitinated CSB from damaged chromatin.

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Section: Volume 291 • Number 14 • April 1 2016supporting

confidence: 84%

Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin

Zhu

Wani

et al. 2016

Journal of Biological Chemistry

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“…These observations suggest that the CS proteins have other functions as well, and evidence has been provided for several other roles,5 25 including the repair of oxidative damage in DNA26–29 and roles in mitochondrial DNA metabolism 30–33. A recent elegant study, using both whole brains and cultured cells, identified a crucial role for the CS proteins in expression of neuronal genes and thereby in neuronal differentiation 34. Similar conclusions have been reached from a study in which induced pluripotent stem cell-derived neuronal cells from patients with CS had reduced transcription of many neural-specific genes 35.…”

Section: Introductionmentioning

confidence: 55%

Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

et al. 2018

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By identifying >70 novel homozygous or compound heterozygous genetic variants in 124 patients with CS with different disease severity and ethnic backgrounds, we considerably broaden the and mutation spectrum responsible for CS. Besides providing information relevant for diagnosis of and genetic counselling for this devastating disorder, this study improves the definition of the puzzling genotype-phenotype relationships in patients with CS.

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“…Additionally, we treated the knockdown cells with the PARP inhibitor PJ34. To validate the results, we included gene expression array data from the cerebellum of human CS patients and their controls from a recently published study (19). Notably, hierarchical clustering showed an association between the CS patients and the transcription inhibitor treatments, despite batch and tissue differences.…”

Section: Significancementioning

confidence: 99%

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Scheibye‐Knudsen

Tseng

Jensen

et al. 2016

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

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Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.Cockayne syndrome | aging | polymerase I transcription | nucleolus | CSA | CSB

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Dysregulation of gene expression as a cause of Cockayne syndrome neurological disease

Cited by 91 publications

References 36 publications

Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin

Valosin-containing Protein (VCP)/p97 Segregase Mediates Proteolytic Processing of Cockayne Syndrome Group B (CSB) in Damaged Chromatin

Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

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