טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAbed Mona
SubjectRegulation of Genetic Networks by a SUMO-Targeted
Ubiquitin Ligase
DepartmentDepartment of Medicine
Supervisor Professor Amir )Oryan )Orian
Full Thesis textFull thesis text - English Version


Abstract

Transcriptional cofactors are essential for proper embryonic development yet the mechanisms that regulate context-selective cofactor association with their corresponding transcription factor or that may regulate cofactor activity itself are largely unknown. We hypothesized that a post-transcriptional event or mechanism could regulate selective co-factor recruitment. Indeed, we identified a cofactor in Drosophila, Degringolade (Dgrn), which encodes a RING finger/E3 ubiquitin ligase and dictates co-factor association during development.  Dgrn and its mammalian ortholog RNF4 are SUMO Targeted Ubiquitin Ligases (STUbLs). STUbLs bind to SUMOylated proteins via their SUMO-Interaction Motif (SIM) domains and facilitate substrate ubiquitylation.  Here we show that Dgrn is a negative regulator of the repressor Hairy and its co-repressor Groucho (Gro/TLE) during embryonic segmentation and neurogenesis. Genetically, we find that dgrn heterozygosity suppresses hairy mutant phenotypes and embryonic lethality.  Mechanistically Dgrn functions as a molecular selector: it targets Hairy for SUMO-independent ubiquitylation that inhibits the recruitment of its co-repressor Gro, without affecting the recruitment of its other cofactors or Hairy’s stability. Concomitantly, Dgrn specifically targets SUMOylated-Gro for sequestration and antagonizes Gro functions in transcription and in vivo. Our findings suggest that by targeting SUMOylated-Gro, Dgrn serves as a molecular switch that regulates cofactor recruitment and function during development. Since Gro/TLE proteins are conserved universal co-repressors, this may be a general paradigm used to regulate the Gro/TLE co-repressors in other developmental processes.