Sunkel, C. | Search bioRxiv

bioRxiv2026

Elevated MPS1 converts the fibrous corona into a source of chromosomal instability in colon cancer

Chromosomal instability (CIN), characterised by recurrent chromosome mis-segregation, fuels intratumour heterogeneity and tumour evolution. Yet, its proximal molecular causes remain ill-defined. Tumour-scale genomic and transcriptomic analyses associate MPS1 overexpression with CIN in colon carcinomas. Consistently, CIN+ patient-derived colon cancer cells (PCCCs) display elevated MPS1, frequent merotelic kinetochore-microtubule attachments and lagging chromosomes that are suppressed by partial MPS1 inhibition. Conversely, ectopic MPS1 overexpression in otherwise stable near-diploid cells phenocopies these defects, inducing micronuclei formation and karyotypic divergence. Mechanistically, MPS1 overactivity maintains ROD phosphorylation at Thr13/Ser15, continuously sustaining fibrous corona assembly despite mature end-on attachments. 3D-STED microscopy reveals split-interface configurations in which microtubules from opposing poles engage the canonical outer-kinetochore surface and a spatially distinct corona domain, explaining how merotely forms and persists into anaphase. Disrupting corona assembly restores chromosome segregation fidelity in MPS1-overexpressing RPE-1 cells and in CIN+ PCCCs. Together, our findings establish MPS1 overexpression as a driver of CIN and uncover how oncogenic transcriptional rewiring of mitotic signalling converts a transient microtubule-capture structure into a pathological source of merotely and chromosome mis-segregation in colon cancer.

cell biology↗

bioRxiv2019

Mps1 releases Mad1 from nuclear pores to ensure a robust mitotic checkpoint and accurate chromosome segregation

The strength of the Spindle Assembly Checkpoint (SAC) depends on the amount of the Mad1-C-Mad2 heterotetramer at kinetochores but also on its binding to Megator/Tpr at nuclear pore complexes (NPCs) during interphase. However, the molecular underpinnings controlling the spatiotemporal redistribution of Mad1-C-Mad2 as cells progress into mitosis remain elusive. Here, we show that Mps1-mediated phosphorylation of Megator/Tpr abolishes its interaction with Mad1 in vitro and in Drosophila cells. Timely activation of Mps1 during prophase triggers Mad1 release from NPCs, which we find to be required for competent kinetochore recruitment of Mad1-C-Mad2 and robust checkpoint response. Importantly, preventing Mad1 binding to Megator/Tpr rescues the fidelity of chromosome segregation and aneuploidy in larval neuroblasts of Drosophila mps1-null mutants. Our findings demonstrate that the subcellular localization of Mad1 is stringently coordinated with cell cycle progression by kinetochore-extrinsic activity of Mps1. This ensures that both NPCs in interphase and kinetochores in mitosis can generate anaphase inhibitors to efficiently preserve genomic stability.

cell biology↗