Lab research summary Büchele

Lab research summary Dr. Gabriele Büchel

Neuroendocrine tumors like childhood neuroblastoma can be driven by amplification of MYCN. For protection of degradation by the proteasome system MYCN is stabilized by Aurora-A. MYCN also forms complexes with TFIIIC, RAD21 and TOP2A. This newly discovered complex is required for MYCN-dependent pause release of RNA Polymerase II (RNAPII). During S-phase Aurora-A displaces the MYCN/TFIIIC complex, inhibits pause release of RNAPII and consecutively prevents replication/transcription conflicts. The MYCN/Aurora-A complex can be disrupted by small molecules like MLN8237 and treatment with those inhibitors shows therapeutical efficacy in human neuroblastoma. We hypothesize that MYC-driven tumors are dependent on Aurora-A to avoid replication/transcription conflicts. We therefore work on improving therapeutic strategies using Aurora-A inhibitors in combination with inhibitors targeting different enzymes of the replication or transcription machinery.