Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein

Joost Schimmel; Karolin Eifler; Jón Otti Sigurdsson; Sabine A G Cuijpers; Ivo A Hendriks; Matty Verlaan-de Vries; Christian D Kelstrup; Chiara Francavilla; René H Medema; Jesper Velgaard Olsen; Alfred C O Vertegaal

doi:10.1016/j.molcel.2014.02.001

Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein

Joost Schimmel, Karolin Eifler, Jón Otti Sigurdsson, Sabine A G Cuijpers, Ivo A Hendriks, Matty Verlaan-de Vries, Christian D Kelstrup, Chiara Francavilla, René H Medema, Jesper Velgaard Olsen, Alfred C O Vertegaal

The NNF Center for Protein Research

113 Citationer (Scopus)

Abstract

Loss of small ubiquitin-like modification (SUMOylation) in mice causes genomic instability due to the missegregation of chromosomes. Currently, little is known about the identity of relevant SUMO target proteins that are involved in this process and about global SUMOylation dynamics during cell-cycle progression. We performed a large-scale quantitative proteomics screen to address this and identified 593 proteins to be SUMO-2 modified, including the Forkhead box transcription factor M1 (FoxM1), a key regulator of cell-cycle progression and chromosome segregation. SUMOylation of FoxM1 peaks during G2 and M phase, when FoxM1 transcriptional activity is required. We found that a SUMOylation-deficient FoxM1 mutant was less active compared to wild-type FoxM1, implying that SUMOylation of the protein enhances its transcriptional activity. Mechanistically, SUMOylation blocks the dimerization of FoxM1, thereby relieving FoxM1 autorepression. Cells deficient for FoxM1 SUMOylation showed increased levels of polyploidy. Our findings contribute to understanding the role of SUMOylation during cell-cycle progression.

Originalsprog	Engelsk
Tidsskrift	Molecular Cell
Vol/bind	53
Udgave nummer	6
Sider (fra-til)	1053-1066
ISSN	1097-2765
DOI	https://doi.org/10.1016/j.molcel.2014.02.001
Status	Udgivet - 20 mar. 2014

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10.1016/j.molcel.2014.02.001

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Schimmel, J., Eifler, K., Sigurdsson, J. O., Cuijpers, S. A. G., Hendriks, I. A., Verlaan-de Vries, M., Kelstrup, C. D., Francavilla, C., Medema, R. H., Olsen, J. V., & Vertegaal, A. C. O. (2014). Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein. Molecular Cell, 53(6), 1053-1066. https://doi.org/10.1016/j.molcel.2014.02.001

Schimmel, J, Eifler, K, Sigurdsson, JO, Cuijpers, SAG, Hendriks, IA, Verlaan-de Vries, M, Kelstrup, CD, Francavilla, C, Medema, RH, Olsen, JV & Vertegaal, ACO 2014, 'Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein', Molecular Cell, bind 53, nr. 6, s. 1053-1066. https://doi.org/10.1016/j.molcel.2014.02.001

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title = "Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein",

abstract = "Loss of small ubiquitin-like modification (SUMOylation) in mice causes genomic instability due to the missegregation of chromosomes. Currently, little is known about the identity of relevant SUMO target proteins that are involved in this process and about global SUMOylation dynamics during cell-cycle progression. We performed a large-scale quantitative proteomics screen to address this and identified 593 proteins to be SUMO-2 modified, including the Forkhead box transcription factor M1 (FoxM1), a key regulator of cell-cycle progression and chromosome segregation. SUMOylation of FoxM1 peaks during G2 and M phase, when FoxM1 transcriptional activity is required. We found that a SUMOylation-deficient FoxM1 mutant was less active compared to wild-type FoxM1, implying that SUMOylation of the protein enhances its transcriptional activity. Mechanistically, SUMOylation blocks the dimerization of FoxM1, thereby relieving FoxM1 autorepression. Cells deficient for FoxM1 SUMOylation showed increased levels of polyploidy. Our findings contribute to understanding the role of SUMOylation during cell-cycle progression.",

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AU - Schimmel, Joost

AU - Eifler, Karolin

AU - Sigurdsson, Jón Otti

AU - Cuijpers, Sabine A G

AU - Hendriks, Ivo A

AU - Verlaan-de Vries, Matty

AU - Kelstrup, Christian D

AU - Francavilla, Chiara

AU - Medema, René H

AU - Olsen, Jesper Velgaard

AU - Vertegaal, Alfred C O

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N2 - Loss of small ubiquitin-like modification (SUMOylation) in mice causes genomic instability due to the missegregation of chromosomes. Currently, little is known about the identity of relevant SUMO target proteins that are involved in this process and about global SUMOylation dynamics during cell-cycle progression. We performed a large-scale quantitative proteomics screen to address this and identified 593 proteins to be SUMO-2 modified, including the Forkhead box transcription factor M1 (FoxM1), a key regulator of cell-cycle progression and chromosome segregation. SUMOylation of FoxM1 peaks during G2 and M phase, when FoxM1 transcriptional activity is required. We found that a SUMOylation-deficient FoxM1 mutant was less active compared to wild-type FoxM1, implying that SUMOylation of the protein enhances its transcriptional activity. Mechanistically, SUMOylation blocks the dimerization of FoxM1, thereby relieving FoxM1 autorepression. Cells deficient for FoxM1 SUMOylation showed increased levels of polyploidy. Our findings contribute to understanding the role of SUMOylation during cell-cycle progression.

AB - Loss of small ubiquitin-like modification (SUMOylation) in mice causes genomic instability due to the missegregation of chromosomes. Currently, little is known about the identity of relevant SUMO target proteins that are involved in this process and about global SUMOylation dynamics during cell-cycle progression. We performed a large-scale quantitative proteomics screen to address this and identified 593 proteins to be SUMO-2 modified, including the Forkhead box transcription factor M1 (FoxM1), a key regulator of cell-cycle progression and chromosome segregation. SUMOylation of FoxM1 peaks during G2 and M phase, when FoxM1 transcriptional activity is required. We found that a SUMOylation-deficient FoxM1 mutant was less active compared to wild-type FoxM1, implying that SUMOylation of the protein enhances its transcriptional activity. Mechanistically, SUMOylation blocks the dimerization of FoxM1, thereby relieving FoxM1 autorepression. Cells deficient for FoxM1 SUMOylation showed increased levels of polyploidy. Our findings contribute to understanding the role of SUMOylation during cell-cycle progression.

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DO - 10.1016/j.molcel.2014.02.001

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JF - Molecular Cell

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Uncovering SUMOylation Dynamics during Cell-Cycle Progression Reveals FoxM1 as a Key Mitotic SUMO Target Protein

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