Leave no sister behind

Recent work published in Cell Reports and Developmental Cell from Sen et al., Orr et al., and Papini et al., demonstrates that midzone-based Aurora B resolves chromosome segregation errors during anaphase

Delaying the final cut: A close encounter of checkpoint kinases at the midbody

How chromatin bridges are relayed to the chromosomal passenger complex (CPC) during mammalian cell division is unknown. In this issue, Petsalaki and Zachos (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202008029) show that the DNA damage checkpoint kinases ATM and Chk2 signal to the CPC to associate with a pool of cytoskeletal regulators, MKLP2-Cep55, in the midbody center and to delay abscission

Щодо утворення сімейств атомарних радіальних базисних функцій

Наведено схему побудови сімейств атомарних радіальних базисних функцій, які є нескінченно диференційовними фінітними розв'язками функціонально-диференціальних рівнянь, породжених операторами Лапласа та Гельмгольца.The scheme of building a family of atomic radial basis functions which are infinitely differentiable finite solutions of the functional-differential equations containing the Laplace and Helmholtz operators is introduced

A highly conserved pocket on PP2A-B56 is required for hSgo1 binding and cohesion protection during mitosis

The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human hSgo1 to the PP2A‐B56 phosphatase through a coiled‐coil (CC) region mediates cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A‐B56‐hSgo1 complex, revealing unanticipated aspects of complex formation and function. We establish that a highly conserved pocket on the B56 regulatory subunit is required for hSgo1 binding and cohesion protection during mitosis in human somatic cells. Consistent with this, we show that hSgo1 blocks the binding of PP2A‐B56 substrates containing a canonical B56 binding motif. We find that PP2A‐B56 bound to hSgo1 dephosphorylates Cdk1 sites on hSgo1 itself to modulate cohesin interactions. Collectively our work provides important insight into cohesion protection during mitosis

Analyse der Spontanmotorik im 1. Lebensjahr: Markerlose 3-D-Bewegungserfassung zur Früherkennung von Entwicklungsstörungen

Children with motor development disorders benefit greatly from early interventions. An early diagnosis in pediatric preventive care (U2–U5) can be improved by automated screening. Current approaches to automated motion analysis, however, are expensive, require lots of technical support, and cannot be used in broad clinical application. Here we present an inexpensive, marker-free video analysis tool (KineMAT) for infants, which digitizes 3‑D movements of the entire body over time allowing automated analysis in the future. Three-minute video sequences of spontaneously moving infants were recorded with a commercially available depth-imaging camera and aligned with a virtual infant body model (SMIL model). The virtual image generated allows any measurements to be carried out in 3‑D with high precision. We demonstrate seven infants with different diagnoses. A selection of possible movement parameters was quantified and aligned with diagnosis-specific movement characteristics. KineMAT and the SMIL model allow reliable, three-dimensional measurements of spontaneous activity in infants with a very low error rate. Based on machine-learning algorithms, KineMAT can be trained to automatically recognize pathological spontaneous motor skills. It is inexpensive and easy to use and can be developed into a screening tool for preventive care for children.Kinder mit motorischer Entwicklungsstörung profitieren von einer frühen Entwicklungsförderung. Eine frühe Diagnosestellung in der kinderärztlichen Vorsorge (U2–U5) kann durch ein automatisiertes Screening verbessert werden. Bisherige Ansätze einer automatisierten Bewegungsanalyse sind jedoch teuer und aufwendig und nicht in der Breite anwendbar. In diesem Beitrag soll ein neues System zur Videoanalyse, das Kinematic Motion Analysis Tool (KineMAT) vorgestellt werden. Es kann bei Säuglingen angewendet werden und kommt ohne Körpermarker aus. Die Methode wird anhand von 7 Patienten mit unterschiedlichen Diagnosen demonstriert. Mit einer kommerziell erhältlichen Tiefenbildkamera (RGB-D[Red-Green-Blue-Depth]-Kamera) werden 3‑minütige Videosequenzen von sich spontan bewegenden Säuglingen aufgenommen und mit einem virtuellen Säuglingskörpermodell (SMIL[Skinned Multi-infant Linear]-Modell) in Übereinstimmung gebracht. Das so erzeugte virtuelle Abbild erlaubt es, beliebige Messungen in 3‑D mit hoher Präzision durchzuführen. Eine Auswahl möglicher Bewegungsparameter wird mit diagnosespezifischen Bewegungsauffälligkeiten zusammengeführt. Der KineMAT und das SMIL-Modell erlauben eine zuverlässige, dreidimensionale Messung der Spontanaktivität bei Säuglingen mit einer sehr niedrigen Fehlerrate. Basierend auf maschinellen Lernalgorithmen kann der KineMAT trainiert werden, pathologische Spontanmotorik automatisiert zu erkennen. Er ist kostengünstig und einfach anzuwenden und soll als Screeninginstrument für die kinderärztliche Vorsorge weiterentwickelt werden

Assembly and Regulation of the Membrane Attack Complex Based on Structures of C5b6 and sC5b9

8 páginas, 4 figuras, 4 figuras suplementarias -- 200-207Activation of the complement system results in formation of membrane attack complexes (MACs), pores that disrupt lipid bilayers and lyse bacteria and other pathogens. Here, we present the crystal structure of the first assembly intermediate, C5b6, together with a cryo-electron microscopy reconstruction of a soluble, regulated form of the pore, sC5b9. Cleavage of C5 to C5b results in marked conformational changes, distinct from those observed in the homologous C3-to-C3b transition. C6 captures this conformation, which is preserved in the larger sC5b9 assembly. Together with antibody labeling, these structures reveal that complement components associate through sideways alignment of the central MAC-perforin (MACPF) domains, resulting in a C5b6-C7-C8b-C8a-C9 arc. Soluble regulatory proteins below the arc indicate a potential dual mechanism in protection from pore formation. These results provide a structural framework for understanding MAC pore formation and regulation, processes important for fighting infections and preventing complement-mediated tissue damage.This work was supported by Council for Chemical Sciences of the Netherlands Organization for Scientific Research (NWO-CW) grant 700.57.010, National Institutes of Health (NIH) grant 1 R01 AI072106-01A1; and European Research Council Advanced Grant 233229 to P.G.; Medical Research Council (MRC) grant G0400775 to S.M.L; Wellcome Trust Programme Grant 068590 to B.P.M.; Wellcome Trust Core Award Grant 090532/Z/09/Z; and a grant from the ‘‘Ramoón Areces’’ Foundation to O.L. O.L. is also supported by the Spanish Ministry of Science and Innovation (SAF2011-22988), ‘‘Red Temaática de Investigación Cooperativa en Cancer (RTICC), Instituto de Salud Carlos III’’ (RD06/0020/1001), Autonomous Region of Madrid (S2010-BMD-2316), and the Human Frontiers Science Program (RGP39/2008). D.B. is supported by EMBO. M.K.P. is supported by the NIH (grant RO1DK35081).Peer reviewe

Changing places: Chromosomal Passenger Complex relocation in early anaphase

The Chromosomal Passenger Complex (CPC) regulates a plethora of processes during multiple stages of nuclear and cytoplasmic division. Early during mitosis, the CPC is recruited to centromeres and kinetochores, and ensures that the duplicated chromosomes become properly connected to microtubules from opposite poles of the mitotic spindle. Progression into anaphase is accompanied by a striking relocation of the CPC from centromeres to the antiparallel microtubule overlaps of the anaphase spindle and to the equatorial cortex. This translocation requires direct interactions of the CPC with the kinesin-6 family member MKLP2/KIF20A, and the inactivation of cyclin B-cyclin-dependent kinase-1 (CDK1). Here, we review recent progress in the regulation of this relocation event. Furthermore, we discuss why the CPC must be relocated during early anaphase in light of recent advances in the functions of the CPC post metaphase

The Ins and Outs of Aurora B Inner Centromere Localization

Error-free chromosome segregation is essential for the maintenance of genomic integrity during cell division. Aurora B, the enzymatic subunit of the Chromosomal Passenger Complex (CPC), plays a crucial role in this process. In early mitosis Aurora B localizes predominantly to the inner centromere, a specialized region of chromatin that lies at the crossroads between the inter-kinetochore and inter-sister chromatid axes. Two evolutionarily conserved histone kinases, Haspin and Bub1, control the positioning of the CPC at the inner centromere and this location is thought to be crucial for the CPC to function. However, recent studies sketch a subtler picture, in which not all functions of the CPC require strict confinement to the inner centromere. In this review we discuss the molecular pathways that direct Aurora B to the inner centromere and deliberate if and why this specific localization is important for Aurora B function

The ins and outs of Aurora B inner centromere localization

Error-free chromosome segregation is essential for the maintenance of genomic integrity during cell division. Aurora B, the enzymatic subunit of the Chromosomal Passenger Complex (CPC), plays a crucial role in this process. In early mitosis Aurora B localizes predominantly to the inner centromere, a specialized region of chromatin that lies at the crossroads between the inter-kinetochore and inter-sister chromatid axes. Two evolutionarily conserved histone kinases, Haspin and Bub1, control the positioning of the CPC at the inner centromere and this location is thought to be crucial for the CPC to function. However, recent studies sketch a subtler picture, in which not all functions of the CPC require strict confinement to the inner centromere. In this review we discuss the molecular pathways that direct Aurora B to the inner centromere and deliberate if and why this specific localization is important for Aurora B function

Inner centromere localization of the CPC maintains centromere cohesion and allows mitotic checkpoint silencing

Faithful chromosome segregation during mitosis requires that the kinetochores of all sister chromatids become stably connected to microtubules derived from opposite spindle poles. How stable chromosome bi-orientation is accomplished and coordinated with anaphase onset remains incompletely understood. Here we show that stable chromosome bi-orientation requires inner centromere localization of the non-enzymatic subunits of the chromosomal passenger complex (CPC) to maintain centromeric cohesion. Precise inner centromere localization of the CPC appears less relevant for Aurora B-dependent resolution of erroneous kinetochore-microtubule (KT-MT) attachments and for the stabilization of bi-oriented KT-MT attachments once sister chromatid cohesion is preserved via knock-down of WAPL. However, Aurora B inner centromere localization is essential for mitotic checkpoint silencing to allow spatial separation from its kinetochore substrate KNL1. Our data infer that the CPC is localized at the inner centromere to sustain centromere cohesion on bi-oriented chromosomes and to coordinate mitotic checkpoint silencing with chromosome bi-orientation