Splicing factors Sf3A2 and Prp31 have direct roles in mitotic chromosome segregation

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Abstract

Several studies have shown that RNAi-mediated depletion of splicing factors (SFs) results in mitotic abnormalities. However, it is currently unclear whether these abnormalities reflect defective splicing of specific pre-mRNAs or a direct role of the SFs in mitosis. Here, we show that two highly conserved SFs, Sf3A2 and Prp31, are required for chromosome segregation in both Drosophila and human cells. Injections of anti-Sf3A2 and anti-Prp31 antibodies into Drosophila embryos disrupt mitotic division within 1 min, arguing strongly against a splicing-related mitotic function of these factors. We demonstrate that both SFs bind spindle microtubules (MTs) and the Ndc80 complex, which in Sf3A2- and Prp31-depleted cells is not tightly associated with the kinetochores; in HeLa cells the Ndc80/HEC1-SF interaction is restricted to the M phase. These results indicate that Sf3A2 and Prp31 directly regulate interactions among kinetochores, spindle microtubules and the Ndc80 complex in both Drosophila and human cells.

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Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes.

Beate Neumann, Thomas Walter, Jean-Karim Hériché … (2010)

Despite our rapidly growing knowledge about the human genome, we do not know all of the genes required for some of the most basic functions of life. To start to fill this gap we developed a high-throughput phenotypic screening platform combining potent gene silencing by RNA interference, time-lapse microscopy and computational image processing. We carried out a genome-wide phenotypic profiling of each of the approximately 21,000 human protein-coding genes by two-day live imaging of fluorescently labelled chromosomes. Phenotypes were scored quantitatively by computational image processing, which allowed us to identify hundreds of human genes involved in diverse biological functions including cell division, migration and survival. As part of the Mitocheck consortium, this study provides an in-depth analysis of cell division phenotypes and makes the entire high-content data set available as a resource to the community.

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Genes required for mitotic spindle assembly in Drosophila S2 cells.

Gohta Goshima, Roy Wollman, Sarah Goodwin … (2007)

The formation of a metaphase spindle, a bipolar microtubule array with centrally aligned chromosomes, is a prerequisite for the faithful segregation of a cell's genetic material. Using a full-genome RNA interference screen of Drosophila S2 cells, we identified about 200 genes that contribute to spindle assembly, more than half of which were unexpected. The screen, in combination with a variety of secondary assays, led to new insights into how spindle microtubules are generated; how centrosomes are positioned; and how centrioles, centrosomes, and kinetochores are assembled.

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Drosophila Aurora B Kinase Is Required for Histone H3 Phosphorylation and Condensin Recruitment during Chromosome Condensation and to Organize the Central Spindle during Cytokinesis

Régis Giet, David Glover (2001)

Aurora/Ipl1-related kinases are a conserved family of enzymes that have multiple functions during mitotic progression. Although it has been possible to use conventional genetic analysis to dissect the function of aurora, the founding family member in Drosophila (Glover, D.M., M.H. Leibowitz, D.A. McLean, and H. Parry. 1995. Cell. 81:95–105), the lack of mutations in a second aurora-like kinase gene, aurora B, precluded this approach. We now show that depleting Aurora B kinase using double-stranded RNA interference in cultured Drosophila cells results in polyploidy. aurora B encodes a passenger protein that associates first with condensing chromatin, concentrates at centromeres, and then relocates onto the central spindle at anaphase. Cells depleted of the Aurora B kinase show only partial chromosome condensation at mitosis. This is associated with a reduction in levels of the serine 10 phosphorylated form of histone H3 and a failure to recruit the Barren condensin protein onto chromosomes. These defects are associated with abnormal segregation resulting from lagging chromatids and extensive chromatin bridging at anaphase, similar to the phenotype of barren mutants (Bhat, M.A., A.V. Philp, D.M. Glover, and H.J. Bellen. 1996. Cell. 87:1103–1114.). The majority of treated cells also fail to undertake cytokinesis and show a reduced density of microtubules in the central region of the spindle. This is accompanied by a failure to correctly localize the Pavarotti kinesin-like protein, essential for this process. We discuss these conserved functions of Aurora B kinase in chromosome transmission and cytokinesis.

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Author and article information

Contributors

Fioranna Renda

Daniel Hayward

Antonella Palena

Jack Chen

Silvia Bonaccorsi

James G Wakefield

Maurizio Gatti:

ORCID: http://orcid.org/0000-0003-3777-300X

Maria Patrizia Somma:

ORCID: http://orcid.org/0000-0002-7585-3484

Jon Pines: Role: Reviewing Editor

Anna Akhmanova: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 26 November 2018

Publication date Collection: 2018

Volume: 7

Electronic Location Identifier: e40325

Affiliations

[1 ]deptIstituto di Biologia e Patologia Molecolari del CNR Sapienza Università di Roma RomaItaly

[2 ]deptDipartimento di Biologia e Biotecnologie “C. Darwin” Sapienza Università di Roma RomaItaly

[3 ]deptBiosciences/Living Systems Institute, College of Life and Environmental Sciences University of Exeter ExeterUnited Kingdom

Institute of Cancer Research Research United Kingdom

Utrecht University Netherlands

Institute of Cancer Research Research United Kingdom

Author notes

[‡]

New York State Department of Health, Wadsworth Center, New York, United States.

[†]

These authors contributed equally to this work.

Author information

Maurizio Gatti http://orcid.org/0000-0003-3777-300X

Maria Patrizia Somma http://orcid.org/0000-0002-7585-3484

Article

Publisher ID: 40325

DOI: 10.7554/eLife.40325

PMC ID: 6287947

PubMed ID: 30475206

SO-VID: 4532f734-bffd-490d-ab17-52da93b7eb9e

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 22 July 2018

Date accepted : 14 November 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;

Award ID: IG16020

Award Recipient : Maurizio Gatti

Funded by: Ministero dell'Istruzione, dell'Università e della Ricerca;

Award Recipient : Silvia Bonaccorsi

Funded by: FundRef http://dx.doi.org/10.13039/501100000268, Biotechnology and Biological Sciences Research Council;

Award ID: BB/K017837/1

Award Recipient : James G Wakefield

Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;

Award ID: IG20528

Award Recipient : Maurizio Gatti

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

Author impact statement Extensive cytological and biochemical analyses show that the conserved Sf3A2 and Prp31 splicing factors bind microtubules and the Ndc80 complex, playing direct mitotic functions in both Drosophila and human mitosis.

ScienceOpen disciplines: Life sciences

Keywords: sf3a2,prp31,ndc80,mitosis,drosophila,hela cells,d. melanogaster

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: sf3a2, prp31, ndc80, mitosis, drosophila, hela cells, d. melanogaster

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Splicing factors Sf3A2 and Prp31 have direct roles in mitotic chromosome segregation

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Most cited references 65

Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes.

Genes required for mitotic spindle assembly in Drosophila S2 cells.

Drosophila Aurora B Kinase Is Required for Histone H3 Phosphorylation and Condensin Recruitment during Chromosome Condensation and to Organize the Central Spindle during Cytokinesis

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