Cockayne syndrome b maintains neural precursor function

Sacco, Raffaele; Tamblyn, Laura; Rajakulendran, Nishani; Bralha, Fernando N.; Tropepe, Vincent; Laposa, Rebecca R.

doi:10.1016/j.dnarep.2012.11.004

Cited by 11 publications

(9 citation statements)

References 99 publications

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“…Consistent with the premature degeneration of mesenchymal progenitor cells, CS-MSCs exhibit decreased cell proliferation, accelerated senescence, and compromised differentiation ability towards osteoblasts, chondrocytes and white adipocytes, which may constitute one of the causes of the observed defects in the musculoskeletal system. In addition, in agreement with previous reports showing confounding defects in the neural system in CS patients (Cleaver et al, 2009;Natale, 2011;Laugel, 2013;Sacco et al, 2013;Ciaffardini et al, 2014;Vessoni et al, 2016), our data indicated severe DNA repair defects and increased susceptibility to UV-induced apoptosis in CS-iPSC-derived NSCs, therefore providing in-depth mechanistic insights into CS-associated neurological disorders.…”

Section: Discussionsupporting

confidence: 92%

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

Wang

Min

et al. 2019

Protein Cell

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Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic genecorrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and

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Section: Discussionsupporting

confidence: 92%

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

Wang

Min

et al. 2019

Protein Cell

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“…Collectively, these findings appear to be relevant to explain the molecular basis of at least some of the neurological symptoms reported in CS patients. Although earlier studies have addressed this aspect in double XP/CS knockout mouse model system, 48, 49, 50 our study is the first to our knowledge to explore the role of CSB in neurogenesis using a human model system.…”

Section: Discussionmentioning

confidence: 99%

“…50 It was previously established that the neurological symptoms in CSB-deficient mice are not as severe as in humans and that CSB mouse model system does not recapitulate the human CSB phenotype. Severe neurological symptoms in human CSB patients can only be induced in mice after functional inactivation of csb in combination with xpc (xeroderma pigmentosum complementation group C) gene.…”

Section: Discussionmentioning

confidence: 99%

The cockayne syndrome B protein is essential for neuronal differentiation and neuritogenesis

et al. 2014

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Cockayne syndrome (CS) is a progressive developmental and neurodegenerative disorder resulting in premature death at childhood and cells derived from CS patients display DNA repair and transcriptional defects. CS is caused by mutations in csa and csb genes, and patients with csb mutation are more prevalent. A hallmark feature of CSB patients is neurodegeneration but the precise molecular cause for this defect remains enigmatic. Further, it is not clear whether the neurodegenerative condition is due to loss of CSB-mediated functions in adult neurogenesis. In this study, we examined the role of CSB in neurogenesis by using the human neural progenitor cells that have self-renewal and differentiation capabilities. In this model system, stable CSB knockdown dramatically reduced the differentiation potential of human neural progenitor cells revealing a key role for CSB in neurogenesis. Neurite outgrowth, a characteristic feature of differentiated neurons, was also greatly abolished in CSB-suppressed cells. In corroboration with this, expression of MAP2 (microtubule-associated protein 2), a crucial player in neuritogenesis, was also impaired in CSB-suppressed cells. Consistent with reduced MAP2 expression in CSB-depleted neural cells, tandem affinity purification and chromatin immunoprecipitation studies revealed a potential role for CSB in the assembly of transcription complex on MAP2 promoter. Altogether, our data led us to conclude that CSB has a crucial role in coordinated regulation of transcription and chromatin remodeling activities that are required during neurogenesis.

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“…In addition, spectral karyotyping analysis of TC-NER defective Ercc6(−/−) ESCs exhibits increased complex exchanges that involves multiple chromosome interactions [52]. Moreover, ERCC6-mediated DNA repair is also important for the self-renewal of embryonic NSCs after UV induced DNA damage [53].…”

Section: Regulation Of Ner In Stem Cellsmentioning

confidence: 99%

DNA repair fidelity in stem cell maintenance, health, and disease

Mani

Reddy

Palle

2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Stem cells are a sub population of cell types that form the foundation of our body, and have the potential to replicate, replenish and repair limitlessly to maintain the tissue and organ homeostasis. Increased lifetime and frequent replication set them vulnerable for both exogenous and endogenous agents-induced DNA damage compared to normal cells. To counter these damages and preserve genetic information, stem cells have evolved with various DNA damage response and repair mechanisms. Furthermore, upon experiencing irreparable DNA damage, stem cells mostly prefer early senescence or apoptosis to avoid the accumulation of damages. However, the failure of these mechanisms leads to various diseases, including cancer. Especially, given the importance of stem cells in early development, DNA repair deficiency in stem cells leads to various disabilities like developmental delay, premature aging, sensitivity to DNA damaging agents, degenerative diseases, etc. In this review, we have summarized the recent update about how DNA repair mechanisms are regulated in stem cells and their association with disease progression and pathogenesis.

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Cockayne syndrome b maintains neural precursor function

Cited by 11 publications

References 99 publications

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction

The cockayne syndrome B protein is essential for neuronal differentiation and neuritogenesis

DNA repair fidelity in stem cell maintenance, health, and disease

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