The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability.
Myc-induced SUN domain-containing protein (Misu or NSun2) is a nucleolar RNA methyltransferase important for c-Myc-induced proliferation in skin, but the mechanisms by which Misu contributes to cell cycle progression are unknown. In this study, we demonstrate that Misu translocates from the nucleoli in interphase to the spindle in mitosis as an RNA-protein complex that includes 18S ribosomal RNA. Functionally, depletion of Misu caused multiple mitotic defects, including formation of unstructured spindles, multipolar spindles, and chromosome missegregation, leading to aneuploidy and cell death. The presence of both RNA and Misu is required for correct spindle assembly, and this process is independent of active translation. Misu might mediate its function at the spindle by recruiting nucleolar and spindle-associated protein (NuSAP), an essential microtubule-stabilizing and bundling protein. We further identify NuSAP as a novel direct target gene of c-Myc. Collectively, our results suggest a novel mechanism by which c-Myc promotes proliferation by stabilizing the mitotic spindle in fast-dividing cells via Misu and NuSAP.
Hussain
Shobbir
S
Wellcome Trust Centre for Stem Cell Research, University of Cambridge, England, UK.
Benavente
Sandra Blanco
SB
Nascimento
Elisabete
E
Dragoni
Ilaria
I
Kurowski
Agata
A
Gillich
Astrid
A
Humphreys
Peter
P
Frye
Michaela
M
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000201:enzymology*; D006801:Humans; D047468:Immunoprecipitation; D007399:Interphase; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins; D008870:Microtubules / Q000201:enzymology; D008938:Mitosis; D009336:Necrosis; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000378:metabolism; D008941:Spindle Apparatus / Q000201:enzymology*; D014404:Tubulin / Q000378:metabolism
D008869:Microtubule-Associated Proteins; C000709213:NUSAP1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D012337:RNA, Ribosomal, 18S; D014404:Tubulin; D008780:Methyltransferases; C513146:Misu protein, mouse; C515610:NSUN2 protein, human