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

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• SUMOylation is a critical post-translational modification regulating diverse cellular processes.
• The essential functions of SUMOylation in maintaining genome stability and cell proliferation are not fully understood.
• Ultrafine DNA bridges (UFBs) pose a threat to genome integrity during cell division.

Purpose of the Study:

• To elucidate the essential roles of SUMOylation in cell proliferation.
• To identify pathways that become indispensable for cell survival upon SUMOylation inhibition.
• To understand the mechanism by which NIP45 and SUMOylation prevent mitotic failure.

Main Methods:

• Genome-scale CRISPR-Cas9 screens were employed to identify essential genes under conditions of SUMOylation inhibition.
• Functional assays were used to investigate the roles of NIP45, SUMOylation, and the BTRR-PICH pathway in DNA catenane resolution.
• The study utilized techniques to assess DNA damage, cell cycle progression, and cytokinesis.

Main Results:

• SUMOylation inhibition renders the BLM-TOP3A-RMI1-RMI2 (BTRR)-PICH pathway and NIP45 indispensable for cell proliferation.
• NIP45, in conjunction with SUMOylation, establishes an interphase pathway that converts DNA catenanes into double-strand breaks (DSBs).
• This NIP45-mediated pathway, independent of TOP2, promotes SUMOylation of factors like the SLX4 complex, facilitating catenane resolution and preventing mitotic catastrophe.

Conclusions:

• SUMOylation is essential for cell proliferation by facilitating the resolution of toxic DNA catenanes.
• Two distinct pathways, NIP45-dependent and BTRR-PICH-dependent, are crucial for resolving DNA catenanes and preventing mitotic failure.
• NIP45 acts via its SUMO-like domains to promote SUMOylation and DNA catenane conversion, highlighting a novel role for SUMOylation in genome stability.