Matrin3 regulates mitotic spindle dynamics by controlling alternative splicing of CDC14B

Matrin3 is an RNA-binding protein that regulates diverse RNA-related processes, including mRNA splicing. Although Matrin3 has been intensively studied in neurodegenerative diseases, its function in cancer remains unclear. Here, we report Matrin3-mediated regulation of mitotic spindle dynamics in colorectal cancer (CRC) cells. We comprehensively identified RNAs bound and regulated by Matrin3 in CRC cells and focused on CDC14B, one of the top Matrin3 targets. Matrin3 knockdown results in increased inclusion of an exon containing a premature termination codon in the CDC14B transcript and simultaneous down-regulation of the standard CDC14B transcript. Knockdown of CDC14B phenocopies the defects in mitotic spindle dynamics upon Matrin3 knockdown, and the elongated and misoriented mitotic spindle observed upon Matrin3 knockdown are rescued upon overexpression of CDC14B, suggesting that CDC14B is a key downstream effector of Matrin3. Collectively, these data reveal a role for the Matrin3/CDC14B axis in control of mitotic spindle dynamics. [Display omitted] •Matrin3 loss reduces cancer cell proliferation•Matrin3 promotes proper target mRNA processing•Matrin3 loss results in decreased CDC14B mRNA expression•Matrin3-dependent CDC14B reduction results in abnormal mitotic spindle dynamics Muys et al. find that the RNA-binding protein Matrin3—best characterized for its role in neurodegenerative diseases—affects cancer cell proliferation and mitotic spindle dynamics by binding and promoting proper processing of the mRNA encoding CDC14B, a conserved, key regulator of eukaryotic mitotic spindle formation.