The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation

Karthik B. Jeganathan, Liviu Malureanu, Jan Van Deursen

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Cdc20 and Cdh1 are the activating subunits of the anaphase-promoting complex (APC), an E3 ubiquitin ligase that drives cells into anaphase by inducing degradation of cyclin B and the anaphase inhibitor securin1. To prevent chromosome missegregation, APC activity directed against these mitotic regulators must be inhibited until all chromosomes are properly attached to the mitotic spindle2. Here we show that in mitosis timely destruction of securin by APC is regulated by the nucleocytoplasmic transport factors Rae1 and Nup98. We show that combined Rae1 and Nup98 haploinsufficiency in mice results in premature separation of sister chromatids, severe aneuploidy and untimely degradation of securin. We find that Rae1 and Nup98 form a complex with Cdh1-activated APC (APCCdh1) in early mitosis and specifically inhibit APCCdh1-mediated ubiquitination of securin. Dissociation of Rae1 and Nup98 from APC coincides with the release of the mitotic checkpoint protein BubR1 from Cdc20-activated APC (APCCdc20) at the metaphase to anaphase transition. Together, our results suggest that Rae1 and Nup98 are temporal regulators of APCCdh1 that maintain euploidy by preventing unscheduled degradation of securin.

Original languageEnglish (US)
Pages (from-to)1036-1039
Number of pages4
JournalNature
Volume438
Issue number7070
DOIs
StatePublished - Dec 15 2005

Fingerprint

Securin
Anaphase-Promoting Complex-Cyclosome
Aneuploidy
Anaphase
Mitosis
Cdh1 Proteins
Cdc20 Proteins
Chromosomes
M Phase Cell Cycle Checkpoints
Cyclin B
Haploinsufficiency
Chromatids
Ubiquitin-Protein Ligases
Cell Nucleus Active Transport
Ubiquitination
Metaphase

ASJC Scopus subject areas

  • General

Cite this

The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. / Jeganathan, Karthik B.; Malureanu, Liviu; Van Deursen, Jan.

In: Nature, Vol. 438, No. 7070, 15.12.2005, p. 1036-1039.

Research output: Contribution to journalArticle

Jeganathan, Karthik B. ; Malureanu, Liviu ; Van Deursen, Jan. / The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. In: Nature. 2005 ; Vol. 438, No. 7070. pp. 1036-1039.
@article{6fb2f737cd6f4eaaac647fe5c2520a6f,
title = "The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation",
abstract = "Cdc20 and Cdh1 are the activating subunits of the anaphase-promoting complex (APC), an E3 ubiquitin ligase that drives cells into anaphase by inducing degradation of cyclin B and the anaphase inhibitor securin1. To prevent chromosome missegregation, APC activity directed against these mitotic regulators must be inhibited until all chromosomes are properly attached to the mitotic spindle2. Here we show that in mitosis timely destruction of securin by APC is regulated by the nucleocytoplasmic transport factors Rae1 and Nup98. We show that combined Rae1 and Nup98 haploinsufficiency in mice results in premature separation of sister chromatids, severe aneuploidy and untimely degradation of securin. We find that Rae1 and Nup98 form a complex with Cdh1-activated APC (APCCdh1) in early mitosis and specifically inhibit APCCdh1-mediated ubiquitination of securin. Dissociation of Rae1 and Nup98 from APC coincides with the release of the mitotic checkpoint protein BubR1 from Cdc20-activated APC (APCCdc20) at the metaphase to anaphase transition. Together, our results suggest that Rae1 and Nup98 are temporal regulators of APCCdh1 that maintain euploidy by preventing unscheduled degradation of securin.",
author = "Jeganathan, {Karthik B.} and Liviu Malureanu and {Van Deursen}, Jan",
year = "2005",
month = "12",
day = "15",
doi = "10.1038/nature04221",
language = "English (US)",
volume = "438",
pages = "1036--1039",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7070",

}

TY - JOUR

T1 - The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation

AU - Jeganathan, Karthik B.

AU - Malureanu, Liviu

AU - Van Deursen, Jan

PY - 2005/12/15

Y1 - 2005/12/15

N2 - Cdc20 and Cdh1 are the activating subunits of the anaphase-promoting complex (APC), an E3 ubiquitin ligase that drives cells into anaphase by inducing degradation of cyclin B and the anaphase inhibitor securin1. To prevent chromosome missegregation, APC activity directed against these mitotic regulators must be inhibited until all chromosomes are properly attached to the mitotic spindle2. Here we show that in mitosis timely destruction of securin by APC is regulated by the nucleocytoplasmic transport factors Rae1 and Nup98. We show that combined Rae1 and Nup98 haploinsufficiency in mice results in premature separation of sister chromatids, severe aneuploidy and untimely degradation of securin. We find that Rae1 and Nup98 form a complex with Cdh1-activated APC (APCCdh1) in early mitosis and specifically inhibit APCCdh1-mediated ubiquitination of securin. Dissociation of Rae1 and Nup98 from APC coincides with the release of the mitotic checkpoint protein BubR1 from Cdc20-activated APC (APCCdc20) at the metaphase to anaphase transition. Together, our results suggest that Rae1 and Nup98 are temporal regulators of APCCdh1 that maintain euploidy by preventing unscheduled degradation of securin.

AB - Cdc20 and Cdh1 are the activating subunits of the anaphase-promoting complex (APC), an E3 ubiquitin ligase that drives cells into anaphase by inducing degradation of cyclin B and the anaphase inhibitor securin1. To prevent chromosome missegregation, APC activity directed against these mitotic regulators must be inhibited until all chromosomes are properly attached to the mitotic spindle2. Here we show that in mitosis timely destruction of securin by APC is regulated by the nucleocytoplasmic transport factors Rae1 and Nup98. We show that combined Rae1 and Nup98 haploinsufficiency in mice results in premature separation of sister chromatids, severe aneuploidy and untimely degradation of securin. We find that Rae1 and Nup98 form a complex with Cdh1-activated APC (APCCdh1) in early mitosis and specifically inhibit APCCdh1-mediated ubiquitination of securin. Dissociation of Rae1 and Nup98 from APC coincides with the release of the mitotic checkpoint protein BubR1 from Cdc20-activated APC (APCCdc20) at the metaphase to anaphase transition. Together, our results suggest that Rae1 and Nup98 are temporal regulators of APCCdh1 that maintain euploidy by preventing unscheduled degradation of securin.

UR - http://www.scopus.com/inward/record.url?scp=30744477013&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=30744477013&partnerID=8YFLogxK

U2 - 10.1038/nature04221

DO - 10.1038/nature04221

M3 - Article

VL - 438

SP - 1036

EP - 1039

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7070

ER -