GRK 2243 "Understanding Ubiquitylation: From Molecular Mechanisms to Disease"

    Project C3

    Role of HUWE1-mediated degradation of MIZ-1 in transcriptional elongation

    Martin Eilers, Sonja Lorenz

    Transcription factors of the MYC family act as global activators of transcriptional elongation and are overexpressed in many human tumors. To understand the molecular and structural basis of MYC protein regulation will be instrumental for the design of new cancer-therapeutic strategies. MYC proteins activate transcription by releasing RNA polymerase from a paused state shortly after initiation of transcription into productive elongation. Transcriptional activation by MYC is antagonized by complex formation between MYC and MIZ1. The factors promoting MIZ1 binding to core promoters and association with MYC are largely unknown. Importantly, MIZ1 is targeted for degradation by the E3 ubiquitin ligase HUWE1, and degradation of MIZ1 is required for transcriptional activation by MYC. This project aims to dissect the interplay between MYC, MIZ1 and HUWE1 in transcriptional elongation using both cell biological and structural approaches.