The SUMO-NIP45 pathway guards against accumulation of toxic DNA catenanes

ABSTRACT: SUMOylation is an essential protein modification that regulates numerous biological processes, but what constitutes its most critical functions in the cell remains unclear. Here, using genome-scale CRISPR-Cas9-based synthetic lethality screens, we show that the BLM-TOP3A-RMI1-RMI2 (BTRR)-PICH pathway, which resolves ultra-fine anaphase DNA bridges (UFBs) arising from catenated DNA structures, and NIP45 (NFATC2IP) display a synthetic lethal interaction in human cells and are essential for proliferation when SUMOylation is impaired. NIP45 and SUMOylation prevent excessive UFB formation that leads to extensive binucleation when BTRR-PICH-dependent UFB resolution is defective, by orchestrating an interphase pathway for converting DNA catenanes into DNA double-strand breaks that trigger G2 arrest via canonical ATM/ATR-dependent DNA damage signaling. NIP45 exerts its crucial function in this pathway by acting as a cofactor for specific SUMOylation processes that are at least in part targeted to the SLX4 multi-nuclease complex, which may facilitate nucleolytic DNA catenane resolution. Our findings establish an essential role of SUMO signaling in underpinning cell proliferation by counteracting the deleterious threat to faithful chromosome segregation posed by toxic DNA catenanes arising in virtually every cell cycle, via non-epistatic NIP45- and BTRR-PICH-dependent pathways.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

SUBMITTER: Ivo Hendriks  

LAB HEAD: Michael Lund Nielsen

PROVIDER: PXD033739 | Pride | 2023-07-21

REPOSITORIES: Pride