A missense mutation in the PISA domain of HsSAS-6 causes autosomal recessive primary microcephaly in a large consanguineous Pakistani family

Asymmetric cell division is essential for normal human brain development. Mutations in several genes encoding centrosomal proteins that participate in accurate cell division have been reported to cause autosomal recessive primary microcephaly (MCPH). By homozygosity mapping including three affected individuals from a consanguineous MCPH family from Pakistan, we delineated a critical region of 18.53 Mb on Chromosome 1p21.3-1p13.1. This region contains the gene encoding HsSAS-6, a centrosomal protein primordial for seeding the formation of new centrioles during the cell cycle. Both next-generation and Sanger sequencing revealed a homozygous c.185T>C missense mutation in the HsSAS-6 gene, resulting in a p.Ile62Thr substitution within a highly conserved region of the PISA domain of HsSAS-6. This variant is neither present in any single-nucleotide polymorphism or exome sequencing databases nor in a Pakistani control cohort. Experiments in tissue culture cells revealed that the Ile62Thr mutant of HsSAS-6 is substantially less efficient than the wild-type protein in sustaining centriole formation. Together, our findings demonstrate a dramatic impact of the mutation p.Ile62Thr on HsSAS-6 function and add this component to the list of genes mutated in primary microcephal

Selective chemical crosslinking reveals a Cep57-Cep63-Cep152 centrosomal complex.

The centrosome functions as the main microtubule-organizing center of animal cells and is crucial for several fundamental cellular processes. Abnormalities in centrosome number and composition correlate with tumor progression and other diseases. Although proteomic studies have identified many centrosomal proteins, their interactions are incompletely characterized. The lack of information on the precise localization and interaction partners for many centrosomal proteins precludes comprehensive understanding of centrosome biology. Here, we utilize a combination of selective chemical crosslinking and superresolution microscopy to reveal novel functional interactions among a set of 31 centrosomal proteins. We reveal that Cep57, Cep63, and Cep152 are parts of a ring-like complex localizing around the proximal end of centrioles. Furthermore, we identify that STIL, together with HsSAS-6, resides at the proximal end of the procentriole, where the cartwheel is located. Our studies also reveal that the known interactors Cep152 and Plk4 reside in two separable structures, suggesting that the kinase Plk4 contacts its substrate Cep152 only transiently, at the centrosome or within the cytoplasm. Our findings provide novel insights into protein interactions critical for centrosome biology and establish a toolbox for future studies of centrosomal proteins

Universitat i societat xarxa : Usos d'Internet en el sistema educatiu superior de Catalunya. Informe final de recerca (volum II)

Aquest estudi analitza -seguint una metodologia quantitativa basada en una mostra representativa de 2.093 professors i 23.864 estudiants i reforçada amb elements qualitatius- la transició que es produeix en el sistema universitari públic català cap a un model més adaptat a les noves necessitats de la societat xarxa. Per a això, es posa especial èmfasi en l'anàlisi dels usos que es fa d'Internet (l'eina clau de la societat xarxa) en el món universitari i en les transformacions que es donen o es donaran com a conseqüència d'aquests usos.El presente estudio analiza -siguiendo una metodología cuantitativa basada en una muestra representativa de 2.093 profesores y 23.864 estudiantes y reforzada con elementos cualitativos- la transición que se produce en el sistema universitario público catalán hacia un modelo más adaptado a las nuevas necesidades de la sociedad red. Para ello, se pone especial énfasis en el análisis de los usos que se dan de Internet (la herramienta clave de la sociedad red) en el mundo universitario así como en las transformaciones que se dan o se darán como consecuencia de éstos.This study analyses -using a quantitative methodology based on a representative sample of 2,093 professors and 23,864 students and reinforced with qualitative elements- the transition that is occurring in the Catalan public university system toward a model that is more adapted to the new needs of the network society. For this, special emphasis is placed on the analysis of the uses made of the Internet (the key tool for the network society) in the university realm as well as the transformations that have occurred or are to occur as a consequence of these uses

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation. Accordingly, PLK4 activity is reduced upon in vitro acetylation of its kinase domain. Moreover, the overexpression of the PLK4 K45R/K46R mutant in cells does not lead to centrosome overamplification, as observed with wild-type PLK4. We also find that impairing KAT2A/2B-acetyltransferase activity results in diminished phosphorylation of PLK4 and in excess centrosome numbers in cells. Overall, our study identifies the global human KAT2A/2B acetylome and uncovers that KAT2A/2B acetylation of PLK4 prevents centrosome amplification

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation. Accordingly, PLK4 activity is reduced upon in vitro acetylation of its kinase domain. Moreover, the overexpression of the PLK4 K45R/K46R mutant in cells does not lead to centrosome overamplification, as observed with wild-type PLK4. We also find that impairing KAT2A/2B-acetyltransferase activity results in diminished phosphorylation of PLK4 and in excess centrosome numbers in cells. Overall, our study identifies the global human KAT2A/2B acetylome and uncovers that KAT2A/2B acetylation of PLK4 prevents centrosome amplification

University and Network Society : research report (synthesis document)

Document de síntesi d'aquest estudi que analitza -seguint una metodologia quantitativa basada en una mostra representativa de 2.093 professors i 23.864 estudiants i reforçada amb elements qualitatius- la transició que es produeix en el sistema universitari públic català cap a un model més adaptat a les noves necessitats de la societat xarxa. Per a això, es posa especial èmfasi en l'anàlisi dels usos que es fa d'Internet (l'eina clau de la societat xarxa) en el món universitari i en les transformacions que es donen o es donaran com a conseqüència d'aquests usos.Documento de síntesis del estudio que analiza -siguiendo una metodología cuantitativa basada en una muestra representativa de 2.093 profesores y 23.864 estudiantes y reforzada con elementos cualitativos- la transición que se produce en el sistema universitario público catalán hacia un modelo más adaptado a las nuevas necesidades de la sociedad red. Para ello, se pone especial énfasis en el análisis de los usos que se dan de Internet (la herramienta clave de la sociedad red) en el mundo universitario así como en las transformaciones que se dan o se darán como consecuencia de éstos.Synthesis document of the study that analyses -using a quantitative methodology based on a representative sample of 2,093 professors and 23,864 students and reinforced with qualitative elements- the transition that is occurring in the Catalan public university system toward a model that is more adapted to the new needs of the network society. For this, special emphasis is placed on the analysis of the uses made of the Internet (the key tool for the network society) in the university realm as well as the transformations that have occurred or are to occur as a consequence of these uses

Universitat i societat xarxa : Usos d'Internet en el sistema educatiu superior de Catalunya. Informe final de recerca (annexos web)

Annexos web de l'estudi que analitza -seguint una metodologia quantitativa basada en una mostra representativa de 2.093 professors i 23.864 estudiants i reforçada amb elements qualitatius- la transició que es produeix en el sistema universitari públic català cap a un model més adaptat a les noves necessitats de la societat xarxa. Per a això, es posa especial èmfasi en l'anàlisi dels usos que es fa d'Internet (l'eina clau de la societat xarxa) en el món universitari i en les transformacions que es donen o es donaran com a conseqüència d'aquests usos.Anexos web del estudio que analiza -siguiendo una metodología cuantitativa basada en una muestra representativa de 2.093 profesores y 23.864 estudiantes y reforzada con elementos cualitativos- la transición que se produce en el sistema universitario público catalán hacia un modelo más adaptado a las nuevas necesidades de la sociedad red. Para ello, se pone especial énfasis en el análisis de los usos que se dan de Internet (la herramienta clave de la sociedad red) en el mundo universitario así como en las transformaciones que se dan o se darán como consecuencia de éstos.This study analyses -using a quantitative methodology based on a representative sample of 2,093 professors and 23,864 students and reinforced with qualitative elements- the transition that is occurring in the Catalan public university system toward a model that is more adapted to the new needs of the network society. For this, special emphasis is placed on the analysis of the uses made of the Internet (the key tool for the network society) in the university realm as well as the transformations that have occurred or are to occur as a consequence of these uses

University and Network Society : research report (synthesis document)

Document de síntesi d'aquest estudi que analitza -seguint una metodologia quantitativa basada en una mostra representativa de 2.093 professors i 23.864 estudiants i reforçada amb elements qualitatius- la transició que es produeix en el sistema universitari públic català cap a un model més adaptat a les noves necessitats de la societat xarxa. Per a això, es posa especial èmfasi en l'anàlisi dels usos que es fa d'Internet (l'eina clau de la societat xarxa) en el món universitari i en les transformacions que es donen o es donaran com a conseqüència d'aquests usos.Documento de síntesis del estudio que analiza -siguiendo una metodología cuantitativa basada en una muestra representativa de 2.093 profesores y 23.864 estudiantes y reforzada con elementos cualitativos- la transición que se produce en el sistema universitario público catalán hacia un modelo más adaptado a las nuevas necesidades de la sociedad red. Para ello, se pone especial énfasis en el análisis de los usos que se dan de Internet (la herramienta clave de la sociedad red) en el mundo universitario así como en las transformaciones que se dan o se darán como consecuencia de éstos.Synthesis document of the study that analyses -using a quantitative methodology based on a representative sample of 2,093 professors and 23,864 students and reinforced with qualitative elements- the transition that is occurring in the Catalan public university system toward a model that is more adapted to the new needs of the network society. For this, special emphasis is placed on the analysis of the uses made of the Internet (the key tool for the network society) in the university realm as well as the transformations that have occurred or are to occur as a consequence of these uses

Universitat i societat xarxa : Usos d'Internet en el sistema educatiu superior de Catalunya. Informe final de recerca (volum II)

Aquest estudi analitza -seguint una metodologia quantitativa basada en una mostra representativa de 2.093 professors i 23.864 estudiants i reforçada amb elements qualitatius- la transició que es produeix en el sistema universitari públic català cap a un model més adaptat a les noves necessitats de la societat xarxa. Per a això, es posa especial èmfasi en l'anàlisi dels usos que es fa d'Internet (l'eina clau de la societat xarxa) en el món universitari i en les transformacions que es donen o es donaran com a conseqüència d'aquests usos.El presente estudio analiza -siguiendo una metodología cuantitativa basada en una muestra representativa de 2.093 profesores y 23.864 estudiantes y reforzada con elementos cualitativos- la transición que se produce en el sistema universitario público catalán hacia un modelo más adaptado a las nuevas necesidades de la sociedad red. Para ello, se pone especial énfasis en el análisis de los usos que se dan de Internet (la herramienta clave de la sociedad red) en el mundo universitario así como en las transformaciones que se dan o se darán como consecuencia de éstos.This study analyses -using a quantitative methodology based on a representative sample of 2,093 professors and 23,864 students and reinforced with qualitative elements- the transition that is occurring in the Catalan public university system toward a model that is more adapted to the new needs of the network society. For this, special emphasis is placed on the analysis of the uses made of the Internet (the key tool for the network society) in the university realm as well as the transformations that have occurred or are to occur as a consequence of these uses

Universitat i societat xarxa : Usos d'Internet en el sistema educatiu superior de Catalunya. Informe final de recerca (volum I)

Aquest estudi analitza -seguint una metodologia quantitativa basada en una mostra representativa de 2.093 professors i 23.864 estudiants i reforçada amb elements qualitatius- la transició que es produeix en el sistema universitari públic català cap a un model més adaptat a les noves necessitats de la societat xarxa. Per a això, es posa especial èmfasi en l'anàlisi dels usos que es fa d'Internet (l'eina clau de la societat xarxa) en el món universitari i en les transformacions que es donen o es donaran com a conseqüència d'aquests usos.El presente estudio analiza -siguiendo una metodología cuantitativa basada en una muestra representativa de 2.093 profesores y 23.864 estudiantes y reforzada con elementos cualitativos- la transición que se produce en el sistema universitario público catalán hacia un modelo más adaptado a las nuevas necesidades de la sociedad red. Para ello, se pone especial énfasis en el análisis de los usos que se dan de Internet (la herramienta clave de la sociedad red) en el mundo universitario así como en las transformaciones que se dan o se darán como consecuencia de éstos.This study analyses -using a quantitative methodology based on a representative sample of 2,093 professors and 23,864 students and reinforced with qualitative elements- the transition that is occurring in the Catalan public university system toward a model that is more adapted to the new needs of the network society. For this, special emphasis is placed on the analysis of the uses made of the Internet (the key tool for the network society) in the university realm as well as the transformations that have occurred or are to occur as a consequence of these uses