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Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis.

ABSTRACT: The mitotic spindle checkpoint monitors proper bipolar attachment of chromosomes to the mitotic spindle. Previously, depletion of the novel kinetochore complex Ska1/Ska2 was found to induce a metaphase delay. By using bioinformatics, we identified C13orf3, predicted to associate with kinetochores. Recently, three laboratories independently indentified C13orf3 as an additional Ska complex component, and therefore we adopted the name Ska3. We found that cells depleted of Ska3 by RNAi achieve metaphase alignment but fail to silence the spindle checkpoint or enter anaphase. After hours of metaphase arrest, chromatids separate but retain robust kinetochore-microtubule attachments. Ska3-depleted cells accumulate high levels of the checkpoint protein Bub1 at kinetochores. Ska3 protein accumulation at kinetochores in prometaphase is dependent on Sgo1 protein. Sgo1, which accumulates at the centromeres earlier, in prophase, is not dependent on Ska3. Sgo1-depleted cells show a stronger premature chromatid separation phenotype than those depleted of Ska3. We hypothesize that Ska3 functions to coordinate checkpoint signaling from the microtubule binding sites within a kinetochore by laterally linking the individual binding sites. We suggest that this network plays a major role in silencing the spindle checkpoint when chromosomes are aligned at metaphase to allow timely anaphase onset and mitotic exit.

SUBMITTER: Daum JR

PROVIDER: S-EPMC2783354 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis.

Daum John R JR Wren Jonathan D JD Daniel Jeremy J JJ Sivakumar Sushama S McAvoy Jennifer N JN Potapova Tamara A TA Gorbsky Gary J GJ

Current biology : CB 20090730 17

The mitotic spindle checkpoint monitors proper bipolar attachment of chromosomes to the mitotic spindle. Previously, depletion of the novel kinetochore complex Ska1/Ska2 was found to induce a metaphase delay. By using bioinformatics, we identified C13orf3, predicted to associate with kinetochores. Recently, three laboratories independently indentified C13orf3 as an additional Ska complex component, and therefore we adopted the name Ska3. We found that cells depleted of Ska3 by RNAi achieve metap ...[more]

PMID: 19646878

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Project description:Chromosome segregation errors in human oocytes are the leading cause of birth defects, and the risk of aneuploid pregnancy increases dramatically as women age. Accurate segregation demands that sister chromatid cohesion remain intact for decades in human oocytes, and gradual loss of the original cohesive linkages established in fetal oocytes is proposed to be a major cause of age-dependent segregation errors. Here we demonstrate that maintenance of meiotic cohesion in Drosophila oocytes during prophase I requires an active rejuvenation program, and provide mechanistic insight into the molecular events that underlie rejuvenation. Gal4/UAS inducible knockdown of the cohesion establishment factor Eco after meiotic S phase, but before oocyte maturation, causes premature loss of meiotic cohesion, resulting in destabilization of chiasmata and subsequent missegregation of recombinant homologs. Reduction of individual cohesin subunits or the cohesin loader Nipped B during prophase I leads to similar defects. These data indicate that loading of newly synthesized replacement cohesin rings by Nipped B and establishment of new cohesive linkages by the acetyltransferase Eco must occur during prophase I to maintain cohesion in oocytes. Moreover, we show that rejuvenation of meiotic cohesion does not depend on the programmed induction of meiotic double strand breaks that occurs during early prophase I, and is therefore mechanistically distinct from the DNA damage cohesion re-establishment pathway identified in G2 vegetative yeast cells. Our work provides the first evidence that new cohesive linkages are established in Drosophila oocytes after meiotic S phase, and that these are required for accurate chromosome segregation. If such a pathway also operates in human oocytes, meiotic cohesion defects may become pronounced in a woman's thirties, not because the original cohesive linkages finally give out, but because the rejuvenation program can no longer supply new cohesive linkages at the same rate at which they are lost.

Dataset Information

Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis.

Publications

Ska3 is required for spindle checkpoint silencing and the maintenance of chromosome cohesion in mitosis.

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