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.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Schimmel
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
authors.forename: Karolin
authors.initials: K
authors.lastname: Eifler
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Jón Otti
authors.initials: JO
authors.lastname: Sigurðsson
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
authors.forename: Sabine A G
authors.initials: SA
authors.lastname: Cuijpers
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
authors.forename: Ivo A
authors.initials: IA
authors.lastname: Hendriks
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
authors.forename: Matty
authors.initials: M
authors.lastname: Verlaan-de Vries
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Kelstrup
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Chiara
authors.initials: C
authors.lastname: Francavilla
authors.affiliation: Department of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address: jesper.olsen@cpr.ku.dk.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands. Electronic address: vertegaal@lumc.nl.
authors.forename: Alfred C O
authors.initials: AC
authors.lastname: Vertegaal
mesh_terms: D000595:Amino Acid Sequence; D002453:Cell Cycle / Q000235:genetics*; D020090:Chromosome Segregation; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics* / Q000378:metabolism; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins