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

Mueller, M.; Eing, L.; Uhl, L.; Schmitz, M.; Kaneva, I.; Byrne, D. P.; Fleischhauer, D.; Burgess, S. G.; Fischer, S.; Gebauer, N.; Nancy-Portebois, V.; Kaltheuner, I. H.; Ha, S. A.; Schuelein-Voelk, C.; Solvie, D.; Richards, M. W.; Vidal, R.; Brand, M.; Papadopoulos, D.; Bayliss, R. W.; Eyers, P. A.; Eyers, C. E.; Geyer, M.; Eilers, M.; Buechel, G.

doi:10.1101/2025.01.15.633177

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bioRxiv · 10.1101/2025.01.15.633177

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

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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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Mueller, M., Eing, L., Uhl, L., Schmitz, M., Kaneva, I., Byrne, D. P., Fleischhauer, D., Burgess, S. G., Fischer, S., Gebauer, N., Nancy-Portebois, V., Kaltheuner, I. H., Ha, S. A., Schuelein-Voelk, C., Solvie, D., Richards, M. W., Vidal, R., Brand, M., Papadopoulos, D., Bayliss, R. W., Eyers, P. A., Eyers, C. E., Geyer, M., Eilers, M., Buechel, G.. 2025-01-19. The MYCN/Aurora-A complex is a cyclin activating kinase for CDK12. https://doi.org/10.1101/2025.01.15.633177

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