The SUMO–NIP45 pathway processes toxic DNA catenanes to prevent mitotic failure

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SUMOylation regulates numerous cellular processes, but what represents the essential functions of this protein modification remains unclear. To address this, we performed genome-scale CRISPR–Cas9-based screens, revealing that the BLM-TOP3A-RMI1-RMI2 (BTRR)-PICH pathway, which resolves ultrafine anaphase DNA bridges (UFBs) arising from catenated DNA structures, and the poorly characterized protein NIP45/NFATC2IP become indispensable for cell proliferation when SUMOylation is inhibited. We demonstrate that NIP45 and SUMOylation orchestrate an interphase pathway for converting DNA catenanes into double-strand breaks (DSBs) that activate the G2 DNA-damage checkpoint, thereby preventing cytokinesis failure and binucleation when BTRR-PICH-dependent UFB resolution is defective. NIP45 mediates this new TOP2-independent DNA catenane resolution process via its SUMO-like domains, promoting SUMOylation of specific factors including the SLX4 multi-nuclease complex, which contributes to catenane conversion into DSBs. Our findings establish that SUMOylation exerts its essential role in cell proliferation by enabling resolution of toxic DNA catenanes via nonepistatic NIP45- and BTRR-PICH-dependent pathways to prevent mitotic failure.

TidsskriftNature Structural and Molecular Biology
Sider (fra-til)1303-1313
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank D. Durocher (Lunenfeld-Tanenbaum Research Institute, University of Toronto, Canada), A. J. Holland (Johns Hopkins University School of Medicine, MA, USA), A. Blackford (University of Oxford, UK), J. Moffat (University of Toronto, Canada), H. Piwnica-Worms (MD Anderson Cancer Center, University of Texas), C. Cardoso (Technical University (TU) of Darmstadt, Germany), P.-H. Gaillard (Aix Marseille University, France) and J. Rouse (University of Dundee, UK) for providing reagents, J. Lukas for critical reading of the manuscript and members of the Mailand laboratory for helpful discussions. We thank M. Olivieri and D. Durocher for help with implementing genome-scale CRISPR–Cas9 screening, G. de la Cruz for assistance with flow cytometry and M. Michaut and H. Neil of the Genomics Platform at Novo Nordisk Foundation Center for Protein Research and Center for Stem Cell Medicine for technical support and use of instruments. Data processing and analysis were performed using the DeiC National Life Science Supercomputer at Technical University of Denmark ( ). This work was supported by grants from the Novo Nordisk Foundation (grant nos. NNF14CC0001 (to M.L.N., J.N. and N.M.) and NNF18OC0030752 (to N.M.)), Independent Research Fund Denmark (grant nos. 7016-00055B and 0134-00048B (to N.M.)), Lundbeck Foundation (grant no. R223-2016-281 (to N.M.)), Nordea Foundation (to I.D.H.) and Danish National Research Foundation (grant no. DNRF-115 (to I.D.H.)).

Publisher Copyright:
© 2023, The Author(s).

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