Browsing by Subject "CENTROSOME"

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  • Oswald, Evelyn; Kirschberg, Matthias; Aubin, Francois; Alonso, Angel; Hufbauer, Martin; Akguel, Baki; Auvinen, Eeva (2019)
    Human papillomaviruses (HPVs) of genus betapapillomavirus (betaHPV) are implicated in skin carcinogenesis, but their exact role in keratinocyte transformation is poorly understood. We show an interaction of HPV5 and HPV8 oncoproteins E6 and E7 with the nuclear mitotic apparatus protein 1 (NuMA). Binding of E6 or E7 to NuMA induces little aneuploidy, cell cycle alterations, or aberrant centrosomes. Intracellular localization of NuMA is not altered by E6 and E7 expression in 2D cultures. However, the localization profile is predominantly cytoplasmic in 3D organotypic skin models. Both viral proteins colocalize with NuMA in interphase cells, while only E7 colocalizes with NuMA in mitotic cells. Intriguingly, a small subset of cells shows E7 at only one spindle pole, whereas NuMA is present at both poles. This dissimilar distribution of E7 at the spindle poles may alter cell differentiation, which may in turn be relevant for betaHPV-induced skin carcinogenesis.
  • Einarsdottir, Elisabet; Svensson, Idor; Darki, Fahimeh; Peyrard-Janvid, Myriam; Lindvall, Jessica M.; Ameur, Adam; Jacobsson, Christer; Klingberg, Torkel; Kere, Juha; Matsson, Hans (2015)
    Developmental dyslexia is the most common learning disorder in children. Problems in reading and writing are likely due to a complex interaction of genetic and environmental factors, resulting in reduced power of studies of the genetic factors underlying developmental dyslexia. Our approach in the current study was to perform exome sequencing of affected and unaffected individuals within an extended pedigree with a familial form of developmental dyslexia. We identified a two-base mutation, causing a p.R229L amino acid substitution in the centrosomal protein 63 kDa (CEP63), co-segregating with developmental dyslexia in this pedigree. This mutation is novel, and predicted to be highly damaging for the function of the protein. 3D modelling suggested a distinct conformational change caused by the mutation. CEP63 is localised to the centrosome in eukaryotic cells and is required for maintaining normal centriole duplication and control of cell cycle progression. We found that a common polymorphism in the CEP63 gene had a significant association with brain white matter volume. The brain regions were partly overlapping with the previously reported region influenced by polymorphisms in the dyslexia susceptibility genes DYX1C1 and KIAA0319. We hypothesise that CEP63 is particularly important for brain development and might control the proliferation and migration of cells when those two events need to be highly coordinated.
  • Gabriel, Elke; Ramani, Anand; Karow, Ulrike; Gottardo, Marco; Natarajan, Karthick; Gooi, Li Ming; Goranci-Buzhala, Gladiola; Krut, Oleg; Peters, Franziska; Nikolic, Milos; Kuivanen, Suvi; Hasu, Essi; Smura, Teemu; Vapalahti, Olli; Papantonis, Argyris; Schmidt-Chanasit, Jonas; Riparbelli, Maria; Callaini, Giuliano; Kroenke, Martin; Utermoehlen, Olaf; Gopalakrishnan, Jay (2017)
    The recent Zika virus (ZIKV) epidemic is associated with microcephaly in newborns. Although the connection between ZIKV and neurodevelopmental defects is widely recognized, the underlying mechanisms are poorly understood. Here we show that two recently isolated strains of ZIKV, an American strain from an infected fetal brain (FB-GWUH-2016) and a closely-related Asian strain (H/PF/2013), productively infect human iPSC-derived brain organoids. Both of these strains readily target to and replicate in proliferating ventricular zone (VZ) apical progenitors. The main phenotypic effect was premature differentiation of neural progenitors associated with centrosome perturbation, even during early stages of infection, leading to progenitor depletion, disruption of the VZ, impaired neurogenesis, and cortical thinning. The infection pattern and cellular outcome differ from those seen with the extensively passaged ZIKV strain MR766. The structural changes we see after infection with these more recently isolated viral strains closely resemble those seen in ZIKV-associated microcephaly.
  • Balestra, Fernando R.; Dominguez-Calvo, Andres; Wolf, Benita; Busso, Coralie; Buff, Alizee; Averink, Tessa; Lipsanen-Nyman, Marita; Huertas, Pablo; Rios, Rosa M.; Gönczy, Pierre (2021)
    TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule-organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity.