Systematic Analysis in<i>Caenorhabditis elegans</i>Reveals that the Spindle Checkpoint Is Composed of Two Largely Independent Branches

Essex, Anthony; Dammermann, Alexander; Lewellyn, Lindsay; Oegema, Karen; Desai, Arshad

doi:10.1091/mbc.e08-10-1047

Cited by 92 publications

(141 citation statements)

References 86 publications

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“…However, these studies could not distinguish whether this phenotype was specifically due to Mad1 depletion or just a consequence of a compromised SAC, because the phenotype of inactivated Mad2 also generates highly abnormal anaphases in cultured mammalian cells. On the other hand, Mad1 inactivation has no effect at all in sensitive mitotic assays of the early Caenorhabditis elegans embryo (Essex et al, 2009;Kitagawa, 2009). This might be a consequence of the holocentric nature of worm chromosomes.…”

Section: Discussionmentioning

confidence: 98%

A mitotic role for Mad1 beyond the spindle checkpoint

Emre

Terracol

Poncet

et al. 2011

Journal of Cell Science

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SummaryUnattached kinetochores generate an anaphase inhibitor, through the spindle assembly checkpoint (SAC), that allows cells more time to establish proper kinetochore-microtubule (K-MT) linkages and thus avoid aneuploidy. Mad1 is the receptor for Mad2 at kinetochores, where it catalyzes the formation of Mad2-Cdc20 complexes, an essential part of the anaphase inhibitor, but whether it has any other mitotic function is unknown. We have generated a mad1-null mutation in Drosophila. This mutant is SAC defective and Mad2 is no longer localized to either nuclear envelope or kinetochores, but it displays normal basal mitotic timing. Unlike mad2 mutants, which have relatively normal mitoses, mad1 anaphases show high frequencies of lagging chromatids, at least some of which are caused by persistent merotelic linkages. A transgene expressing GFP-Mad1 rescues both the SAC and the anaphase defects. In an attempt to separate the SAC function from the mitotic function, we made a mad1 transgene with a mutated Mad2-binding domain. Surprisingly, this transgene failed to complement the anaphase phenotype. Thus, Mad1 has activity promoting proper K-MT attachments in addition to its checkpoint function. This activity does not require the presence of Mad2, but it does depend in some unknown way on key residues in the Mad2-binding domain of Mad1.

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Section: Discussionmentioning

confidence: 98%

A mitotic role for Mad1 beyond the spindle checkpoint

Emre

Terracol

Poncet

et al. 2011

Journal of Cell Science

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“…Vertebrate Aurora B is required for efficient localization of Mps1 (Vigneron et al, 2004;Santaguida et al, 2010;Saurin et al, 2011), and Aurora B and Mps1 are required for the localization of other SAC proteins. In all organisms examined, Bub1 is upstream of Mad1 and Mad2 (Sharp-Baker and Chen, 2001;Gillett et al, 2004;Meraldi et al, 2004;Essex et al, 2009). Most variable in the hierarchy are Mad3 and BubR1, which coincides with the stronger evolutionary divergence compared to other SAC proteins (Musacchio and Salmon, 2007).…”

Section: The Network Of Sac Protein Localization Dependenciesmentioning

confidence: 95%

Mph1 kinetochore localization is crucial and upstream in the hierarchy of spindle assembly checkpoint protein recruitment to kinetochores

Heinrich

Windecker

Hustedt

et al. 2012

Journal of Cell Science

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SummaryThe spindle assembly checkpoint (SAC) blocks entry into anaphase until all chromosomes have stably attached to the mitotic spindle through their kinetochores. The checkpoint signal originates from unattached kinetochores, where there is an enrichment of SAC proteins. Whether the enrichment of all SAC proteins is crucial for SAC signaling is unclear. Here, we provide evidence that, in fission yeast, recruitment of the kinase Mph1 is of vital importance for a stable SAC arrest. An Mph1 mutant that eliminates kinetochore enrichment abolishes SAC signaling, whereas forced recruitment of this mutant to kinetochores restores SAC signaling. In bub3D cells, the SAC is functional when only Mph1 and the Aurora kinase Ark1, but no other SAC proteins, are enriched at kinetochores. We analyzed the network of dependencies for SAC protein localization to kinetochores and identify a three-layered hierarchy with Ark1 and Mph1 on top, Bub1 and Bub3 in the middle, and Mad3 as well as the Mad1-Mad2 complex at the lower end of the hierarchy. If Mph1 is artificially recruited to kinetochores, Ark1 becomes dispensable for SAC activity. Our results highlight the crucial role of Mph1 at kinetochores and suggest that the Mad1-Mad2 complex does not necessarily need to be enriched at kinetochores for functional SAC signaling.

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“…Such a basic timing mechanism might be useful in the very early embryonic cell cycles, which often do not have a spindle assembly checkpoint, or only a very weak checkpoint. Indeed, Caenorhabditis elegans embryos have only a very weak spindle checkpoint, that can only delay anaphase onset by a few minutes (Essex et al 2009;Kitagawa 2009;Kitagawa and Rose 1999), while Xenopus egg extracts do not have a functional spindle checkpoint at all, unless one increases massively the nucleus to cytoplasm ratio (Chen et al 1996;Minshull et al 1994). Nevertheless, these extracts contain all the spindle assembly checkpoint proteins, suggesting that they fulfill a function at this stage of embryonic development.…”

Section: A Checkpoint or Timing Mechanism?mentioning

confidence: 99%

The Spindle Assembly Checkpoint: Clock or Domino?

Medina-Redondo

Meraldi

2011

Results and Problems in Cell Differentiation

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In each cell division, the newly duplicated chromosomes must be evenly distributed between the sister cells. Errors in this process during meiosis or mitosis are equally fatal: improper segregation of the chromosome 21 during human meiosis leads to Down syndrome (Conley, Aneuploidy: etiology and mechanisms, pp 1985), whereas in somatic cells, aneuploidy has been linked to carcinogenesis, by unbalancing the ratio of oncogenes and tumor suppressors (Holland and Cleveland, Nat Rev Mol Cell Biol 10(7): 478-487, 2009; Yuen et al., Curr Opin Cell Biol 17(6):576-582, 2005). Eukaryotic cells have developed a mechanism, known as the spindle assembly checkpoint, to detect erroneous attachment of chromosomes to the mitotic/meiotic spindle and delay the cell cycle to give enough time to resolve these defects. Research in the last 20 years, has demonstrated that the spindle assembly checkpoint is not only a pure checkpoint pathway, but plays a constitutive role in every cell cycle. Here, we review our current knowledge of how the spindle assembly checkpoint is integrated into the cell cycle machinery, and discuss some of the questions that have to be addressed in the future.

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Systematic Analysis inCaenorhabditis elegansReveals that the Spindle Checkpoint Is Composed of Two Largely Independent Branches

Cited by 92 publications

References 86 publications

A mitotic role for Mad1 beyond the spindle checkpoint

A mitotic role for Mad1 beyond the spindle checkpoint

Mph1 kinetochore localization is crucial and upstream in the hierarchy of spindle assembly checkpoint protein recruitment to kinetochores

The Spindle Assembly Checkpoint: Clock or Domino?

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