Dissecting transcription termination and RNA sorting in MYCN-driven tumors

Introduction

The inherent stresses arising from oncogenic transcription can be counteracted by premature termination, which removes RNA polymerase II (RNAPII) from DNA and enables the degradation of aberrant nascent RNA by the nuclear exosome. When overexpressed, the MYCN oncoprotein fuels the growth of aggressive tumors by globally binding active promoters and invariably enhancing RNAPII transcription.

Key Discoveries

However, I have made two key discoveries showing that the function of MYCN is not restricted to gene activation:

1. Interaction with the Exosome: MYCN interacts with the exosome and prevents conflicts of RNAPII with replication forks to avert lethal DNA damage.
2. Binding Nascent RNAs: MYCN globally leaves promoters and directly binds nascent RNAs, which are then steered to the exosome for decay.

RNA-bound MYCN also forms large protein complexes comprising the ARS2 transcript sorting protein, RNAPII, and termination factors. These findings fundamentally expand MYCN function as they reveal that the oncoprotein exists in competing DNA- and RNA-bound states, with the latter fulfilling a heretofore unknown RNA degrading role.

Project Overview

In TerSor, we will investigate whether RNA-bound MYCN controls termination and RNA sorting processes to counteract aberrant transcription and thereby suppress DNA damage and immune recognition in neuroblastoma cells.

Research Objectives

1. Mapping MYCN RNA-Binding Domains: We will map MYCN RNA-binding domains and test the effects of RNA-binding loss in cells and neuroblastoma mouse models.
2. Exploring Regulation of Termination and RNA Sorting: We will explore MYCN-driven regulation of termination and RNA sorting machineries.
3. Investigating DNA Damage Mitigation: We will investigate how the exosome and MYCN mitigate DNA damage and the accumulation of immunogenic transcripts.
4. Studying MYCN’s Interface Structure: Finally, we will study the structure of MYCN’s interface with exosome targeting complexes.

Conclusion

Collectively, we will use cutting-edge approaches to profoundly further our understanding of MYCN oncogenic function by studying how the oncoprotein’s newly discovered ability to bind RNA maintains the genomic integrity and immune evasion of aggressive tumors.