The SUMO–NIP45 pathway processes toxic DNA catenanes to prevent mitotic failure
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The SUMO–NIP45 pathway processes toxic DNA catenanes to prevent mitotic failure. / Hertz, Emil P.T.; Vega, Ignacio Alonso de; Kruse, Thomas; Wang, Yiqing; Hendriks, Ivo A.; Bizard, Anna H.; Eugui-Anta, Ania; Hay, Ronald T.; Nielsen, Michael L.; Nilsson, Jakob; Hickson, Ian D.; Mailand, Niels.
In: Nature Structural and Molecular Biology, Vol. 30, 2023, p. 1303-1313.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The SUMO–NIP45 pathway processes toxic DNA catenanes to prevent mitotic failure
AU - Hertz, Emil P.T.
AU - Vega, Ignacio Alonso de
AU - Kruse, Thomas
AU - Wang, Yiqing
AU - Hendriks, Ivo A.
AU - Bizard, Anna H.
AU - Eugui-Anta, Ania
AU - Hay, Ronald T.
AU - Nielsen, Michael L.
AU - Nilsson, Jakob
AU - Hickson, Ian D.
AU - Mailand, Niels
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41594-023-01045-0
DO - 10.1038/s41594-023-01045-0
M3 - Journal article
C2 - 37474739
AN - SCOPUS:85165176770
VL - 30
SP - 1303
EP - 1313
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
ER -
ID: 360983590