title: Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity.
abstract: Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions.
authors.affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Gemayel
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Chavali
authors.affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Pougach
authors.affiliation: Structural and Genomic Information Laboratory, IGS UMR7256, Centre National de la Recherche Scientifique, Aix-Marseille Université, Institut de Microbiologie de la Méditerranée (IMM), 13288 Marseille Cedex 9, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Legendre
authors.affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Boeynaems
authors.affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium.
authors.forename: Elisa
authors.initials: E
authors.lastname: van der Zande
authors.affiliation: Department of Medical Protein Research, VIB, 9000 Ghent, Belgium; Department of Biochemistry, Ghent University, 9000 Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Switch Laboratory, VIB, Campus Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Switch Laboratory, VIB, Campus Gasthuisberg, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: M Madan
authors.initials: MM
authors.lastname: Babu
authors.affiliation: Laboratory of Systems Biology, VIB, Gaston Geenslaan 1, 3001 Heverlee, Belgium; Laboratory of Genetics and Genomics, Centre of Microbial and Plant Genetics (CMPG), Department M2S, KU Leuven, Gaston Geenslaan 1, 3001 Heverlee, Belgium. Electronic address: kevin.verstrepen@biw.vib-kuleuven.be.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Verstrepen
mesh_terms: D001483:Base Sequence; D004271:DNA, Fungal / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D005973:Glutamine / Q000737:chemistry; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D020449:Repetitive Sequences, Amino Acid; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
chemical_list: C065455:CYC8 protein, S cerevisiae; D004271:DNA, Fungal; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D005973:Glutamine