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bioRxiv · 10.1101/2025.09.09.675108

Mitotic single-stranded DNA suppression by DDIAS

Xue, Y.·bin Rashed, F.·Mao, D. Y. L.·Abe, K. T.·Lin, Z.-Y.·Setiaputra, D.·Hoeg, L.·Bonnet, C.·Sicheri, F.·Gingras, A.-C.·Durocher, D.
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Abstract

Incomplete DNA replication and chromosome breakage during mitosis pose major threats to chromosome segregation. The CIP2A-TOPBP1 complex acts to mitigate this peril, but its exact role is not yet understood. Here, we report that DDIAS acts as a DNA-binding effector of the CIP2A-TOPBP1 complex. DDIAS directly interacts with TOPBP1 and the disruption of this interaction or inactivation of its single-stranded DNA (ssDNA)-binding ability impairs genome integrity and causes synthetic lethality with BRCA1 and BRCA2 deficiency. DDIAS does not promote the putative end-tethering function of CIP2A-TOPBP1 but rather acts to suppress ssDNA during mitosis. This role is emphasized by a pronounced genetic interaction between the genes coding for DDIAS and DNA polymerase (. We conclude that DDIAS defines a mitotic DNA damage response that mitigates the threat of mitotic ssDNA arising from DNA replication stress, which we infer is a liability to accurate chromosome segregation. (144 words).

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Xue, Y., bin Rashed, F., Mao, D. Y. L., Abe, K. T., Lin, Z.-Y., Setiaputra, D., Hoeg, L., Bonnet, C., Sicheri, F., Gingras, A.-C., Durocher, D.. 2025-09-09. Mitotic single-stranded DNA suppression by DDIAS. https://doi.org/10.1101/2025.09.09.675108

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