Centrosomes catalyze microtubule formation for mitotic spindle assembly 1 . Centrosomes duplicate once per cell cycle in a process controlled the kinase PLK4 2 , 3 . Following chemical PLK4 inhibition, cell division in the absence of centrosome duplication generates centrosome-less cells that exhibit delayed, acentrosomal spindle assembly 4 . Whether PLK4 inhibitors can be leveraged for cancer treatment is not yet clear. Here, we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 accelerates acentrosomal spindle assembly and improves proliferation following PLK4 inhibition, whereas high TRIM37 inhibits acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer 5 – 8 , which renders these cancer types highly sensitive to PLK4 inhibition. TRIM37 inactivation improves acentrosomal mitosis because TRIM37 prevents PLK4 self-assembly into centrosome-independent condensates that serve as ectopic microtubule-organizing centers. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly via a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is a critical determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes, including 17q gain in neuroblastoma and 17q23 amplification in breast cancer, may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.

SUMMARY During M-phase entry in metazoans with open mitosis, the concerted action of mitotic kinases disassembles nuclei and promotes assembly of kinetochores—the primary microtubule attachment sites on chromosomes. At M-phase exit, these major changes in cellular architecture must be reversed. Here, we show that the conserved kinetochore-localized nucleoporin MEL-28/ELYS docks the catalytic subunit of protein phosphatase 1 (PP1c) to direct kinetochore disassembly-dependent chromosome segregation during oocyte meiosis I, and nuclear assembly during the transition from M-phase to interphase. During oocyte meiosis I, MEL-28-PP1c disassembles kinetochores in a timely manner to promote elongation of the acentrosomal spindles that segregate homologous chromosomes. During nuclear assembly, MEL-28 recruits PP1c to the periphery of decondensed chromatin where it directs formation of a functional nuclear compartment. Thus, a pool of phosphatase activity associated with a kinetochore-localized nucleoporin contributes to two key events that occur during M-phase exit in metazoans: kinetochore disassembly and nuclear reassembly.

During animal cell division, the central spindle, an anti-parallel microtubule bundle structure formed between segregating chromosomes during anaphase, cooperates with astral microtubules to position the cleavage furrow. Because the central spindle is the only structure linking the two halves of the mitotic spindle, it is under mechanical tension from dynein-generated cortical pulling forces, which determine spindle positioning and drive chromosome segregation through spindle elongation. The central spindle should be flexible enough for efficient chromosome segregation while maintaining its structural integrity for reliable cytokinesis. How the cell balances these potentially conflicting requirements is poorly understood. Here, we demonstrate that the central spindle in C. elegans embryos has a resilient mechanism for recovery from perturbations by excess tension derived from cortical pulling forces. This mechanism involves the direct interaction of two different types of conserved microtubule bundlers that are crucial for central spindle formation, PRC1 and centralspindlin.