The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12

Mareike Müller; Lorenz Eing; Leonie Uhl; Maximilian Schmitz; Iliyana N. Kaneva; Dominic P. Byrne; Daniel Fleischhauer; Selena G. Burgess; Sophia Fischer; N Gebauer; Vanessa Nancy-Portebois; Ines H. Kaltheuner; Stefanie Ahn Ha; Christina Schülein-Völk; Daniel Solvie; Mark W. Richards; Raphael Silveira Vidal; Matthias Brand; Dimitrios Papadopoulos; Richard W. Bayliss; Patrick A. Eyers; Claire E. Eyers; Matthias Geyer; Martin Eilers; Gabriele Büchel

doi:10.1101/2025.01.15.633177

Cancer BiologybioRxivJan 15, 2025

Preprint

The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12

Mareike Müller iD, Lorenz Eing iD, Leonie Uhl iD, Maximilian Schmitz iD, Iliyana N. Kaneva iD, Dominic P. Byrne iD, Daniel Fleischhauer, Selena G. Burgess iD, Sophia Fischer, N Gebauer, Vanessa Nancy-Portebois, Ines H. Kaltheuner iD, Stefanie Ahn Ha, Christina Schülein-Völk, Daniel Solvie iD, Mark W. Richards iD, Raphael Silveira Vidal iD, Matthias Brand iD, Dimitrios Papadopoulos iD, Richard W. Bayliss iD, Patrick A. Eyers iD, Claire E. Eyers iD, Matthias Geyer iD, Martin Eilers iD, Gabriele Büchel iD

Abstract

Deregulated MYCN is a driver of aggressive pediatric and adult neuroendocrine tumors, but critical oncogenic processes downstream of MYCN remain poorly defined. In neuroblastoma, MYCN interacts with and activates the Aurora-A kinase. Here we show that Aurora-A is a CDK-activating kinase for CDK12 by phosphorylating T893 in the T-loop, thereby enhancing its kinase activity. Aurora-A-dependent activation of CDK12 controls phosphorylation of T4 of RNA polymerase and recruits transcription termination complexes, thereby preventing transcription-replication conflicts. Enhanced crosslinking and immunoprecipitation sequencing reveals that Aurora-A associates with splice sites on nascent RNA. RNA-bound Aurora-A is catalytically inactive. MYCN competes with RNA for binding to Aurora-A and displaces Aurora-A from RNA in cells, promoting its CDK12 kinase activity. Combining Aurora-A and CDK12 inhibition potently suppresses the growth of MYCN-amplified neuroblastoma cells and patient-derived xenografts. Our data demonstrate that an Aurora-A/CDK12-dependent transcription termination pathway is a critical and targetable dependency of MYCN-driven tumors.

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