biostudies-literaturede Haan LAustrian Science Fund FWFRCUK | MRC | Medical Research FoundationKWF Kankerbestrijding (Dutch Cancer Society)Dutch Research Council (NWO)KWF Kankerbestrijding13https://www.ebi.ac.uk/biostudies/studies/S-EPMC12765896biostudies-literatureUnknown17(1)Perturbed DNA replication can lead to incompletely replicated DNA when cells enter mitosis and can interfere with chromosome segregation. Cells therefore require mechanisms to resolve these lesions during mitosis. The CIP2A-TOPBP1 complex is described to tether fragmented DNA molecules during mitosis. Whether CIP2A also functions in processing of incompletely replicated DNA remained unclear. We show that CIP2A-TOPBP1 form large filamentous structures at sites of incomplete DNA replication during mitosis, and that CIP2A-TOPBP1 facilitate the recruitment of SMX tri-nuclease complex members SLX4, MUS81 and XPF-ERCC1. These structures form in proximity to sites of mitotic DNA synthesis, although CIP2A is not required for mitotic DNA synthesis. In addition to its globular and coiled-coil domainNature communicationsCIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions.PMC12765896MR/R017549/112911MC_UU_00016/19FWF - PAT1893225MC_UU_00029/2OCENW.M #21.106VICI 09150182110019van de Kooij Bde Haan LHuis In 't Veld PJGarcia-Lopez AEverts MMol FNvan Vugt MATMde Boer HRMartzios PBakker FJWarner HVlijm RDijt SJChapman JRRuan DfalseCIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions.Perturbed DNA replication can lead to incompletely replicated DNA when cells enter mitosis and can interfere with chromosome segregation. Cells therefore require mechanisms to resolve these lesions during mitosis. The CIP2A-TOPBP1 complex is described to tether fragmented DNA molecules during mitosis. Whether CIP2A also functions in processing of incompletely replicated DNA remained unclear. We show that CIP2A-TOPBP1 form large filamentous structures at sites of incomplete DNA replication during mitosis, and that CIP2A-TOPBP1 facilitate the recruitment of SMX tri-nuclease complex members SLX4, MUS81 and XPF-ERCC1. These structures form in proximity to sites of mitotic DNA synthesis, although CIP2A is not required for mitotic DNA synthesis. In addition to its globular and coiled-coil domain2025-01-01T00:00:00Z2025 Dec2026-06-10T04:59:03.528Z2026-06-10T03:07:43.34ZS-EPMC127658964133093010.1038/s41467-025-66549-3