The mitotic CIP2A-TOPBP1 axis facilitates mitotic pathway choice between MiDAS and MMEJ

Martin, P. R.; Nieminuszczy, J.; Kozik, Z.; Jakub, N.; Lecot, M.; Vorhauser, J.; Lane, K. A.; Kanellou, A.; Mansfeld, J.; Pearl, L. H.; Oliver, A.; Downs, J. A.; Chaudhary, J.; Day, M.; Niedzwiedz, W.

doi:10.1101/2024.11.12.621593

bioRxiv · 10.1101/2024.11.12.621593

The mitotic CIP2A-TOPBP1 axis facilitates mitotic pathway choice between MiDAS and MMEJ

Martin, P. R.·Nieminuszczy, J.·Kozik, Z.·Jakub, N.·Lecot, M.·Vorhauser, J.·Lane, K. A.·Kanellou, A.·Mansfeld, J.·Pearl, L. H.·Oliver, A.·Downs, J. A.·Chaudhary, J.·Day, M.·Niedzwiedz, W.

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Abstract

Mitotic DNA double-strand breaks (DSBs) accumulate in response to replication stress or BRCA1/2 deficiency posing a significant threat to genome stability as repair by non-homologous end-joining (NHEJ) and homologous recombination (HR) is inactivated in mitosis. Mitotic cells instead rely on the mechanisms of microhomology mediated end-joining (MMEJ) and mitotic DNA synthesis (MiDAS). However, how these pathways are regulated in mitosis remains unknown. Here we reveal the CIP2A-TOPBP1 complex facilitates recruitment of SMX complex components to mitotic chromatin marked by CIP2A, through a CDK1-dependent interaction between TOPBP1 BRCT 1/2 and SLX4 phospho-threonine1260, that drives MiDAS. Furthermore, CIP2A promotes the recruitment of Pol{theta} to facilitate mitotic MMEJ. This defines a mechanistic framework for mitotic DSB repair, where simultaneous disruption of MiDAS and MMEJ pathways underpins the synthetic lethality observed in BRCA1/2-deficient cells following CIP2A depletion. These findings provide critical insights into mitotic DNA repair and highlights therapeutic opportunities in HR deficient tumours.

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Martin, P. R., Nieminuszczy, J., Kozik, Z., Jakub, N., Lecot, M., Vorhauser, J., Lane, K. A., Kanellou, A., Mansfeld, J., Pearl, L. H., Oliver, A., Downs, J. A., Chaudhary, J., Day, M., Niedzwiedz, W.. 2024-11-13. The mitotic CIP2A-TOPBP1 axis facilitates mitotic pathway choice between MiDAS and MMEJ. https://doi.org/10.1101/2024.11.12.621593

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