DDIAS is a single-stranded DNA-binding effector of the TOPBP1-CIP2A complex in mitosis

Tsukada, K.; Lototska, L.; Tsukada, A.; Gonenc, I. I.; Sherlaw-Sturrock, C.; Kanade, M.; Oliver, A. W.; Jones, S. E.; Jhujh, S. S.; Bannister, J.; Pouzet, A.; Levy, J.; Ali, A.; Raza, M.; Toft, M.; Iqbal, Z.; Fatima, A.; Miller, T. C.; Stewart, G. S.; Ochs, F.; Blackford, A. N.

doi:10.1101/2025.09.09.675193

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bioRxiv · 10.1101/2025.09.09.675193

DDIAS is a single-stranded DNA-binding effector of the TOPBP1-CIP2A complex in mitosis

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Abstract

DNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segregation in favor of alternative pathways that depend on TOPBP1 and CIP2A, but how they function is still poorly defined. Here, we describe the identification of DDIAS as a mitosis-specific DNA damage response protein. We establish DDIAS as a phosphorylation-dependent component and effector of the TOPBP1-CIP2A complex with single-stranded DNA (ssDNA)-binding activity, and thereby delineate a ssDNA protection mechanism that safeguards chromosome integrity during mitosis, particularly in BRCA-deficient cells. We also identify biallelic inactivating mutations in DDIAS in a patient with a severe neurodevelopmental disorder. These findings highlight for the first time a potential physiological role for the DNA damage response in mitosis.

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Tsukada, K., Lototska, L., Tsukada, A., Gonenc, I. I., Sherlaw-Sturrock, C., Kanade, M., Oliver, A. W., Jones, S. E., Jhujh, S. S., Bannister, J., Pouzet, A., Levy, J., Ali, A., Raza, M., Toft, M., Iqbal, Z., Fatima, A., Miller, T. C., Stewart, G. S., Ochs, F., Blackford, A. N.. 2025-09-10. DDIAS is a single-stranded DNA-binding effector of the TOPBP1-CIP2A complex in mitosis. https://doi.org/10.1101/2025.09.09.675193

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