Bub3–BubR1-dependent sequestration of Cdc20Fizzy at DNA breaks facilitates the correct segregation of broken chromosomes

Derive, Nicolas; Landmann, Cedric; Montembault, Émilie; Claverie, Marie-Charlotte; Pierre-Elies, Priscillia; Goutte-Gattat, Damien; Founounou, Nabila; McCusker, Derek; Royou, Anne

doi:10.1083/jcb.201504059

Cited by 27 publications

(41 citation statements)

References 72 publications

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“…The Spindle Assembly Checkpoint gene BubR1 was recently shown to function as part of a “tether” connecting acentric DNA and its centromere when breaks are induced during Drosophila neuroblast mitosis (Royou et al 2010; Karg et al 2015; Derive et al 2015). Using the I-Cre1 system, an established method of generating an acentric chromosome (Rong et al 2002; Royou et al 2010), we generated acentric X-chromosomes in diploid neuroblasts.…”

Section: Resultsmentioning

confidence: 99%

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Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2

Bretscher

Fox

2016

Developmental Cell

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Conserved DNA damage responses (DDRs) sense genome damage and prevent mitosis of broken chromosomes. How cells lacking DDRs cope with broken chromosomes during mitosis is poorly understood. DDRs are frequently inactivated in cells with extra genomes (polyploidy), suggesting study of polyploidy can reveal how cells with impaired DDRs/genome damage continue dividing. Here, we show continued division and normal organ development occurs in polyploid, DDR-impaired Drosophila papillar cells. As papillar cells become polyploid, they naturally accumulate broken acentric chromosomes, but do not apoptose/arrest the cell cycle. To survive mitosis with acentric chromosomes, papillar cells require Fanconi Anemia proteins FANCD2 and FANCI, and Blm helicase, but not canonical DDR signaling. FANCD2 acts independently of previous S-phases to promote alignment and segregation of acentric DNA produced by double-strand breaks, thus avoiding micronuclei and organ malformation. As polyploidy and impaired DDRs can promote cancer, our findings provide insight into disease-relevant DNA damage tolerance mechanisms.

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Section: Resultsmentioning

confidence: 99%

“…BubR1, Polo, and Aurora B respond to broken chromosomes in Drosophila neuroblasts (Royou et al 2010; Karg et al 2015; Derive et al 2015), and Aurora B and INCENP form heterochromatic DNA threads that segregate achiasmate chromosomes during Drosophila meiosis (Hughes et al 2009). Here, we propose that FANCD2 performs a similar function.…”

Section: Discussionmentioning

confidence: 99%

Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2

Bretscher

Fox

2016

Developmental Cell

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“…Therefore, in order to address this possibility, we prevented BubR1 association to kinetochores by generating a mutation in the glutamate 481 (referred to as bubR1-E481K mutant and homologous to E406 in human) of the Bub3 binding region of BubR1. This conserved residue was previously shown to be essential for the interaction of BubR1 with Bub3 and for the recruitment of BubR1 to kinetochores (Harris et al, 2005; Larsen et al, 2007; Derive et al, 2015). As reported by others in mammalian cells and in Drosophila , the mutation abolished kinetochore recruitment of the BubR1-E481 K construct (data not shown).…”

Section: Resultsmentioning

confidence: 98%

A novel mutation in the N-terminal domain of Drosophila BubR1 affects the spindle assembly checkpoint function of BubR1

2016

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The spindle assembly checkpoint (SAC) is a surveillance mechanism that ensures accurate segregation of chromosomes into two daughter cells. BubR1, a key component of the SAC, also plays a role in the mitotic timing since depletion of BubR1 leads to accelerated mitosis. We previously found that mutation of the KEN1-box domain of Drosophila BubR1 (bubR1-KEN1 mutant) affects the binding of BubR1 to Cdc20, the activating co-factor of the APC/C, and does not accelerate the mitotic timing despite resulting in a defective SAC, which was unlike what was reported in mammalian cells. Here, we show that a mutation in a novel Drosophila short sequence (bubR1-KAN mutant) leads to an accelerated mitotic timing as well as SAC failure. Moreover, our data indicate that the level of Fzy, the Drosophila homolog of Cdc20, recruited to kinetochores is diminished in bubR1-KEN1 mutant cells and further diminished in bubR1-KAN mutant cells. Altogether, our data show that this newly identified Drosophila BubR1 KAN motif is required for a functional SAC and suggest that it may play an important role on Cdc20/Fzy kinetochore recruitment.

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“…Support for this idea comes from live imaging acentrics in which the tether has been compromised through reduced BubR1 function. In these instances, the acentric is often observed far from the metaphase plate (Royou et al, 2010;Derive et al, 2015). Another contributing factor to failed acentric segregation may be diminished anaphase A and B spindle elongation in klp3a mutants (Kwon et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The chromokinesin Klp3a and microtubules facilitate acentric chromosome segregation

Karg

Elting

Vicars

et al. 2017

Journal of Cell Biology

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Bub3–BubR1-dependent sequestration of Cdc20Fizzy at DNA breaks facilitates the correct segregation of broken chromosomes

Abstract: BubR1 depends on its association with Bub3 to localize on DNA breaks during mitosis, where it sequesters Cdc20Fizzy and induces the inhibition of the APC/C locally, promoting the faithful segregation of broken chromatids.

Cited by 27 publications

References 72 publications

Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2

Proliferation of Double-Strand Break-Resistant Polyploid Cells Requires Drosophila FANCD2

A novel mutation in the N-terminal domain of Drosophila BubR1 affects the spindle assembly checkpoint function of BubR1

The chromokinesin Klp3a and microtubules facilitate acentric chromosome segregation

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