title: Covalent small ubiquitin-like modifier (SUMO) modification of Maf1 protein controls RNA polymerase III-dependent transcription repression.
abstract: RNA polymerase (pol) III transcribes genes that determine biosynthetic capacity. Induction of these genes is required for oncogenic transformation. The transcriptional repressor, Maf1, plays a central role in the repression of these and other genes that promote oncogenesis. Our studies identify an important new role for SUMOylation in repressing RNA pol III-dependent transcription. We show that a key mechanism by which this occurs is through small ubiquitin-like modifier (SUMO) modification of Maf1 by both SUMO1 and SUMO2. Mutation of each lysine residue revealed that Lys-35 is the major SUMOylation site on Maf1 and that the deSUMOylase, SENP1, is responsible for controlling Maf1K35 SUMOylation. SUMOylation of Maf1 is unaffected by rapamycin inhibition of mammalian target of rapamycin (mTOR) and mTOR-dependent Maf1 phosphorylation. By preventing SUMOylation at Lys-35, Maf1 is impaired in its ability to both repress transcription and suppress colony growth. Although SUMOylation does not alter Maf1 subcellular localization, Maf1K35R is defective in its ability to associate with RNA pol III. This impairs Maf1 recruitment to tRNA gene promoters and its ability to facilitate the dissociation of RNA pol III from these promoters. These studies identify a novel role for SUMOylation in controlling Maf1 and RNA pol III-mediated transcription. Given the emerging roles of SENP1, Maf1, and RNA pol III transcription in oncogenesis, our studies support the idea that deSUMOylation of Maf1 and induction of its gene targets play a critical role in cancer development.
authors.affiliation: Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California and the Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA.
authors.forename: Aarti D
authors.initials: AD
authors.lastname: Rohira
authors.forename: Chun-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Justin R
authors.initials: JR
authors.lastname: Allen
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Johnson
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012320:RNA Polymerase III / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C520535:MAF1 protein, human; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D012320:RNA Polymerase III; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; D008239:Lysine
keywords: Post-translational Modification; RNA Polymerase III; Transcription Factors; Transcription Regulation; Transcription Repressor