SUMO modification of Stra13 is required for repression of cyclin D1 expression and cellular growth arrest

• Published in: PloS one Vol. 7; no. 8; p. e43137
• Main Authors: Wang, Yaju, Rao, Vinay Kumar, Kok, Wai Kay, Roy, Dijendra Nath, Sethi, Sumita, Ling, Belinda Mei Tze, Lee, Martin Beng Huat, Taneja, Reshma
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14-08-2012; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biology; Cell Cycle; Cell Survival; Chlorocebus aethiops; Chromatin; COS Cells; Cyclin D1; Cyclin D1 - biosynthesis; DNA-Binding Proteins - metabolism; Enzymes; Gene expression; Gene Expression Regulation; Gene regulation; Gene silencing; Growth; HEK293 Cells; Helix-loop-helix proteins; Helix-loop-helix proteins (basic); Histone deacetylase; Homeodomain Proteins - metabolism; Humans; Localization; Mice; Molecular Chaperones - metabolism; Mutation; NIH 3T3 Cells; Nuclear Proteins - metabolism; Phase transitions; Physiology; Post-translation; Post-translational modifications; Protein Inhibitors of Activated STAT - metabolism; Protein Processing, Post-Translational; Protein Structure, Tertiary; Proteins; S phase; Senescence; Sumo; SUMO protein; SUMO-1 Protein - metabolism; Transcription factors; Ubiquitin; Singapore
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043137

Stra13, a basic helix-loop-helix (bHLH) transcription factor is involved in myriad biological functions including cellular growth arrest, differentiation and senescence. However, the mechanisms by which its transcriptional activity and function are regulated remain unclear. In this study, we provide evidence that post-translational modification of Stra13 by Small Ubiquitin-like Modifier (SUMO) dramatically potentiates its ability to transcriptionally repress cyclin D1 and mediate G(1) cell cycle arrest in fibroblast cells. Mutation of SUMO acceptor lysines 159 and 279 located in the C-terminal repression domain has no impact on nuclear localization; however, it abrogates association with the co-repressor histone deacetylase 1 (HDAC1), attenuates repression of cyclin D1, and prevents Stra13-mediated growth suppression. HDAC1, which promotes cellular proliferation and cell cycle progression, antagonizes Stra13 sumoylation-dependent growth arrest. Our results uncover an unidentified regulatory axis between Stra13 and HDAC1 in progression through the G(1)/S phase of the cell cycle, and provide new mechanistic insights into regulation of Stra13-mediated transcriptional repression by sumoylation.