Showing papers by "Erich A. Nigg published in 2018"

Once and only once: mechanisms of centriole duplication and their deregulation in disease

Abstract: Centrioles are conserved microtubule-based organelles that form the core of the centrosome and act as templates for the formation of cilia and flagella. Centrioles have important roles in most microtubule-related processes, including motility, cell division and cell signalling. To coordinate these diverse cellular processes, centriole number must be tightly controlled. In cycling cells, one new centriole is formed next to each pre-existing centriole in every cell cycle. Advances in imaging, proteomics, structural biology and genome editing have revealed new insights into centriole biogenesis, how centriole numbers are controlled and how alterations in these processes contribute to diseases such as cancer and neurodevelopmental disorders. Moreover, recent work has uncovered the existence of surveillance pathways that limit the proliferation of cells with numerical centriole aberrations. Owing to this progress, we now have a better understanding of the molecular mechanisms governing centriole biogenesis, opening up new possibilities for targeting these pathways in the context of human disease.

Structural centrosome aberrations promote non‐cell‐autonomous invasiveness

Abstract: Centrosomes are the main microtubule-organizing centers of animal cells. Although centrosome aberrations are common in tumors, their consequences remain subject to debate. Here, we studied the impact of structural centrosome aberrations, induced by deregulated expression of ninein-like protein (NLP), on epithelial spheres grown in Matrigel matrices. We demonstrate that NLP-induced structural centrosome aberrations trigger the escape ("budding") of living cells from epithelia. Remarkably, all cells disseminating into the matrix were undergoing mitosis. This invasive behavior reflects a novel mechanism that depends on the acquisition of two distinct properties. First, NLP-induced centrosome aberrations trigger a re-organization of the cytoskeleton, which stabilizes microtubules and weakens E-cadherin junctions during mitosis. Second, atomic force microscopy reveals that cells harboring these centrosome aberrations display increased stiffness. As a consequence, mitotic cells are pushed out of mosaic epithelia, particularly if they lack centrosome aberrations. We conclude that centrosome aberrations can trigger cell dissemination through a novel, non-cell-autonomous mechanism, raising the prospect that centrosome aberrations contribute to the dissemination of metastatic cells harboring normal centrosomes.

Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability.

Abstract: Although aneuploidy is poorly tolerated during embryogenesis, aneuploidy and whole chromosomal instability (CIN) are common hallmarks of cancer, raising the question of how cancer cells can thrive in spite of chromosome aberrations. Here we present a comprehensive and quantitative proteomics analysis of isogenic DLD-1 colorectal adenocarcinoma cells lines, aimed at identifying cellular responses to changes in ploidy and/or CIN. Specifically, we compared diploid (2N) and tetraploid (4N) cells with posttetraploid aneuploid (PTA) clones and engineered trisomic clones. Our study provides a comparative data set on the proteomes and phosphoproteomes of the above cell lines, comprising several thousand proteins and phosphopeptides. In comparison to the parental 2N line, we observed changes in proteins associated with stress responses and with interferon signaling. Although we did not detect a conspicuous protein signature associated with CIN, we observed many changes in phosphopeptides that relate to fundamental cellular processes, including mitotic progression and spindle function. Most importantly, we found that most changes detectable in PTA cells were already present in the 4N progenitor line. This suggests that activation of mitotic pathways through hyper-phosphorylation likely constitutes an important response to chromosomal burden. In line with this conclusion, cells with extensive chromosome gains showed differential sensitivity toward a number of inhibitors targeting cell cycle kinases, suggesting that the efficacy of anti-mitotic drugs may depend on the karyotype of cancer cells.

The SKP1-Cullin-F-box E3 ligase βTrCP and CDK2 cooperate to control STIL abundance and centriole number.

Abstract: Deregulation of centriole duplication has been implicated in cancer and primary microcephaly. Accordingly, it is important to understand how key centriole duplication factors are regulated. E3 ubiquitin ligases have been implicated in controlling the levels of several duplication factors, including PLK4, STIL and SAS-6, but the precise mechanisms ensuring centriole homeostasis remain to be fully understood. Here, we have combined proteomics approaches with the use of MLN4924, a generic inhibitor of SCF E3 ubiquitin ligases, to monitor changes in the cellular abundance of centriole duplication factors. We identified human STIL as a novel substrate of SCF-βTrCP. The binding of βTrCP depends on a DSG motif within STIL, and serine 395 within this motif is phosphorylated in vivo SCF-βTrCP-mediated degradation of STIL occurs throughout interphase and mutations in the DSG motif causes massive centrosome amplification, attesting to the physiological importance of the pathway. We also uncover a connection between this new pathway and CDK2, whose role in centriole biogenesis remains poorly understood. We show that CDK2 activity protects STIL against SCF-βTrCP-mediated degradation, indicating that CDK2 and SCF-βTrCP cooperate via STIL to control centriole biogenesis.

Structural centrosome aberrations sensitize polarized epithelia to basal cell extrusion

Abstract: Centrosome aberrations disrupt tissue architecture and may confer invasive properties to cancer cells. Here we show that structural centrosome aberrations, induced by overexpression of either Ninein-like protein (NLP) or CEP131/AZI1, sensitize polarized mammalian epithelia to basal cell extrusion. While unperturbed epithelia typically dispose of damaged cells through apical dissemination into luminal cavities, certain oncogenic mutations cause a switch in directionality towards basal cell extrusion, raising the potential for metastatic cell dissemination. Here we report that NLP-induced centrosome aberrations trigger the preferential extrusion of damaged cells towards the basal surface of epithelial monolayers. This switch in directionality from apical to basal dissemination coincides with a profound reorganization of the microtubule cytoskeleton, which in turn prevents the contractile ring repositioning that is required to support extrusion towards the apical surface. While the basal extrusion of cells harbouring NLP-induced centrosome aberrations requires exogenously induced cell damage, structural centrosome aberrations induced by excess CEP131 trigger the spontaneous dissemination of dying cells towards the basal surface from MDCK cysts. Thus, similar to oncogenic mutations, structural centrosome aberrations can favour basal extrusion of damaged cells from polarized epithelia. Assuming that additional mutations may promote cell survival, this process could sensitize epithelia to disseminate potentially metastatic cells.

New Editor-in-Chief-welcome to Simon Boulton!

Abstract: In this first issue of 2018, I am delighted to announce that Professor Simon Boulton will succeed me as Editor-in-Chief of Chromosoma. Simon has been on the board of Associated Editors ofChromosoma since 2011. He is an eminent scientist with broad experience and an outstanding international reputation in the field of DNA repair. Thus, Simon is eminently qualified to leadChromosoma into an exciting future and I am very happy to put the editorial responsibility for this scholarly journal into his hands. I have had the privilege to enjoy 40 years of exploratory science and have acted as Editor-in-Chief for Chromosoma since 2003. Having reached retirement age, I have now decided to close my laboratory, resign from all editorial duties and pursue other interests in life. My thanks go to all the authors, referees and readers of Chromosoma that have contributed to the success of the journal in recent years. I would also like to thank all members of the Editorial Board of Chromosoma, as well as my editorial assistants and the staff at Springer-Nature for a most enjoyable collaboration during the past 15 years. I am confident that Chromosoma will continue to prosper and wish Simon Boulton all the very best for the years to come! Erich Nigg Thanks and all the very best... As I step into the rather large shoes vacated by Prof. Erich Nigg, I would like to extend my heartfelt thanks to Erich for his effort and dedication during his time as Editor-in-Chief at Chromosoma. Erich leaves the journal in a very healthy position, which makes my job easier as I transition from Associate Editor to Editor-in-Chief. However, I am also acutely aware that I have a very difficult act to follow. I am particularly grateful to Erich for his nomination to succeed him in this important role. I was very fortunate to have worked as a visiting scientist in Erich’s department at the Max-PlanckInstitute of Biochemistry (Martinsried) during my second postdoc over 20 years ago. As such, this gives me the opportunity to thank him for his support both in my early career as well as now. I wish him all the very best for a long and fulfilling retirement. Moving forward into 2018, I will endeavour to build on the success that Erich, the Board of Associate Editors and Springer-Nature have brought to Chromosoma over the years. I am very much looking forward to working with our outstanding Board of Associate Editors and hope to expand our expertise into complementary areas where necessary. With recent technological advances in genome editing, Hi-C methods, high-content and high-resolution microscopy and Cryo-EM, this is a particularly exciting time for our field, which I hope will reflect in the continued success of Chromosoma in the years to come. I wish you all the very best for 2018. Simon Boulton