MYCN-dependent Transcription Termination and Stress Resilience of Transcription

• Applicant: Professor Dr. Martin Eilers
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438596161

MYCN is one of three genes of the MYC family and a driving oncogene in many neuroendocrine tumor entities. It encodes a nuclear protein that displays many features of a transcription factor and binds globally to active promoters and many enhancers. Consistently, a large body of literature documents that MYCN, like its counterpart MYC, can both positively and negatively affect the expression of many genes and potentially enhance global transcription rates. It has been difficult, however, to explain the pervasive role of MYC and MYCN in tumorigenesis in terms of changes in expression of its target genes since both proteins have either no or at best very weak effects on expression of the vast majority of genes with MYC/MYCN-bound promoters. As consequence, no consensus model of oncogenic functions of MYC proteins has emerged.We have recently identified the MYCN interactome and studied its dynamics during the cell cycle; this suggested that MYCN proteins co-ordinate transcription elongation with DNA replication. We also found that MYCN can promote premature transcription termination if RNA Polymerase II (RNAPII) stalls. Our unpublished work identifies EXOSC10, a 3'-5´-RNA exonuclease, as a protein that forms a ternary complex with MYCN and RNAPII and may enable MYCN to promote the restart of stalling RNAPII. We speculate from these findings that MYCN specifically coordinates transcription with DNA replication and double-strand break repair and facilitates clearance of promoters if RNAPII stalls due to transcription-induced torsional stress as well as nucleotide imbalances. We hypothesize that the ability to terminate transcription and clear promoters from stalling RNAPII is central to MYCN-dependent oncogenic transformation since it enhances the stress resilience of transcription in tumor cells. The aim of this grant is to explore the underlying mechanisms and test this hypothesis.

• DFG Programme: Research Grants