Andrea Musacchio

..These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression...

..These results shed light on the determinants of kinetochore recruitment of Bub1...

..The structure of the O-Mad2-C-Mad2 conformational dimer is consistent with a catalytic model in which a C-Mad2 template facilitates the binding of O-Mad2 to Cdc20, the target of Mad2 in the spindle checkpoint...

..e., it is purely catalytic. These results surpass previously formulated objections to the Mad2-template model and predict that the release of Mad2 from Cdc20 is an energy-driven process...

..Our biochemical and genetic evidence shows that the interaction of O- and C-Mad2 is essential for the SAC and is conserved in evolution...

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..We also show that the negative effects of p31comet on the SAC are based on its competition with O-Mad2 for C-Mad2 binding...

..Our analysis has important implications for understanding kinetochore organization in different organisms...

..This result suggests that a target of 5-ITu, possibly Haspin itself, may further contribute to SAC signaling downstream of Aurora B...

..The recombinant complex displays normal kinetochore localization upon injection in HeLa cells and is therefore a faithful copy of the endogenous Ndc80 complex...

..These events are linked to the existence of two distinct conformers of Mad2: a closed conformer bound to its kinetochore receptor Mad1 or its target in the checkpoint Cdc20 and an open conformer unbound to these ligands...

..We discuss our results with reference to current models of kinetochore-microtubule attachment and centromere organization...

..We set out to identify small compounds that inhibit kinetochore-microtubule binding for use in kinetochore-spindle interaction studies and to develop them into novel anticancer drugs...

..We discuss how tension-sensitive phenomena, such as attachment correction and stabilization, relate to the SAC and we speculate on the existence of a single pathway linking error correction and SAC activation...

..They also shed light on the relationship between the error correction pathway and the spindle checkpoint and suggest that these processes are coregulated and are likely to share at least a subset of their catalytic machinery...

..Our results support a model in which Aurora B is at the apex of a signalling pyramid whose sensory apparatus promotes the concomitant activation of error correction and checkpoint signalling pathways...

..Our studies unveil a crucial and likely universal link between the inner and outer kinetochore...

..Here, we describe how current work is contributing to unravel the complex endeavors of this essential kinetochore complex...

..Our studies implicate Sgt1 as an essential protein and a critical assembly factor for the mammalian kinetochore, and lend credit to the hypothesis of a kinetochore assembly pathway that is conserved from yeast to man...

..We discuss Mad2 oligomerization and link our discoveries to previous observations related to Mad2 oligomerization...

..Our studies reveal a homeostatic network in which checkpoint-sustaining and -repressing forces oppose each other during mitotic arrest and suggest ways for enhancing the sensitivity of cancer cells to antitubulin chemotherapeutics...

..Here, we take a molecular view on the main challenges hampering this task...

..In this review, we discuss how the molecular organization of the four modules allows a dynamic integration of kinetochore-microtubule attachment with the prevention of chromosome segregation errors and cell-cycle progression...

..Our results uncover a unifying mechanism of inhibitor resistance of protein kinases that might have widespread significance for drug target validation and clinical practice...

..The RZZ, limited to metazoans, probably evolved from the NRZ, exploiting the dynein-binding capacity of ZW10 to direct dynein to kinetochores...

..2385-2399 present an analysis of the recently discovered Spindly/SPDL-1 protein that casts new lights onto the attachment process and the way it relates to the control of cell cycle progression...

..These models add a molecular framework to an old theory that depicts kinetochores as catalysts in the generation of the mitotic checkpoint signal...

..Overall, the structure of the Haspin kinase domain reveals an active conformation that is poised for substrate recognition and phosphorylation in the absence of external regulators...

..Phosphorylation of two serines in the carboxyl terminus of INCENP generates the fully active kinase...

..Removal of sister chromatid cohesion is predicted to cause a fall in tension. Two studies shed light on how cells avoid re-activation of the spindle checkpoint when cohesion is lost...

..Here, we review and integrate findings on the dynamics of checkpoint proteins at kinetochores with structural information about signalling complexes...

..We also show that unlocking the Mad2 C-terminal tail is required for ligand release from Mad2, and that the 'safety belt' mechanism may prolong the lifetime of Mad2-ligand complexes...

..Because gamma-TuRC inhibition leads to pleiotropic spindle defects, which are well known to activate kinetochore-derived checkpoint signaling, we believe that this conclusion is premature...

..Analysis of the cytological and anti-tumor activities of BI 2536, a novel, selective pharmacological inhibitor of Plk1, has connected chemistry and biology to the bedside...

..These findings reveal a key role for the Hec1 N terminus in controlling dynamic behavior of kinetochore microtubules...

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..Furthermore, because the plasticity of the ATP-binding pocket renders Aurora B insensitive to multiple inhibitors, our observations indicate that the drug-resistant Aurora B mutants should be exploited as novel drug targets...