The mitotic protein NuMA plays a spindle-independent role in nuclear formation and mechanics

Abstract

Eukaryotic cells typically form a single, round nucleus after mitosis, and failures to do so can compromise genomic integrity. How mammalian cells form such a nucleus remains incompletely understood. NuMA is a spindle protein whose disruption results in nuclear fragmentation. What role NuMA plays in nuclear integrity, and whether its perceived role stems from its spindle function, are unclear. Here, we use live imaging to demonstrate that NuMA plays a spindle-independent role in forming a single, round nucleus. NuMA keeps the decondensing chromosome mass compact at mitotic exit and promotes a mechanically robust nucleus. NuMA’s C terminus binds DNA in vitro and chromosomes in interphase, while its coiled-coil acts as a central regulatory and structural element: it prevents NuMA from binding chromosomes at mitosis, regulates its nuclear mobility, and is essential for nuclear formation. Thus, NuMA plays a structural role over the cell cycle, building and maintaining the spindle and nucleus, two of the cell’s largest structures.

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

“…To determine whether these nuclear morphology defects depended on the ability of KIF22 to generate forces within the mitotic spindle, cells were treated with nocodazole to depolymerize microtubules and reversine to silence the spindle assembly checkpoint, allowing cells to enter and exit mitosis without assembling a spindle or segregating chromosomes ( Samwer et al, 2017 ; Serra-Marques et al, 2020 ; Figure 6D ). The solidity of nuclei was measured before chromosomes condensed ( Figure 6E ) and after mitotic exit ( Figure 6F ).…”

Nuclear IGF1R interacts with NuMA and regulates 53BP1‑dependent DNA double‑strand break repair in colorectal cancer

“…The NuMA-53BP1 interaction was reported to be located in the nucleoplasm when there is no DSB repair ( 23 ). The fact that IGF1R-NuMA colocalization was not inducible by IR in the present study suggested that the interaction most likely does not occur at the chromatin surrounding the DSB site, despite the structural and chromosome-binding roles of NuMA ( 48 ), as well as the transcription regulatory function of nIGF1R through DNA binding ( 14 ). The mechanism behind IGF1R-NuMA-53BP1 interactions could be either that IGF1R-NuMA and NuMA-53BP1 interactions are mutually exclusive or that they form a tripartite complex.…”

NuMA Deficiency Causes Micronuclei via Checkpoint-Insensitive k-Fiber Minus-End Detachment From Mitotic Spindle Poles

“…18 Multiple studies reported that NuMA dysfunction causes spindle pole-focusing defects, 16,[19][20][21][22][23] lagging chromosomes in anaphase, 24,25 and micronuclei formation in somatic cells. [26][27][28] Although these studies have linked NuMA depletion to chromosomal mis-segregation in mitosis, it has remained difficult to unequivocally attribute micronuclei formation to specific defects during metaphase, especially in terms of SAC satisfaction. In this study, we analyzed dynamic behaviors of chromosomes, kinetochores, checkpoint proteins, microtubules, and centrosomes in HCT116 colon cancer cells after rapidly depleting NuMA by the auxin-inducible degron (AID) system.…”