The TRIM69-MST2 signaling axis regulates centrosome dynamics and chromosome segregation

  • Nucleic Acids Res. 2023 Oct 27;51(19):10568-10589. doi: 10.1093/nar/gkad766.
Yilin Wang  1 ,  Patrik Risteski  2 ,  Yang Yang  1  3 ,  Huan Chen  4 ,  Gaith Droby  1  5 ,  Andrea Walens  3 ,  Deepika Jayaprakash  1  6 ,  Melissa Troester  7 ,  Laura Herring  8 ,  Jonathan Chernoff  9 ,  Iva M Tolić  2 ,  Jessica Bowser  1 ,  Cyrus Vaziri  1  3
Affiliations
  • 1. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 2. Division of Molecular Biology, Ruđer Boskovic Institute, Bijenicka cesta 54, 10000 Zagreb, Croatia.
  • 3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 4. Joint Center for Single Cell Biology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 5. Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 6. Oral and Craniofacial Biomedicine Program, Adam's School of Dentistry, University of North Carolina at Chapel Hill, NC 27599, USA.
  • 7. Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 8. Department of Pharmacology, UNC Proteomics Core Facility, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 9. Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
PMID: 37739411 DOI: 10.1093/nar/gkad766
Abstract

Stringent control of centrosome duplication and separation is important for preventing chromosome instability. Structural and numerical alterations in centrosomes are hallmarks of neoplastic cells and contribute to tumorigenesis. We show that a Centrosome Amplification 20 (CA20) gene signature is associated with high expression of the Tripartite Motif (TRIM) family member E3 ubiquitin Ligase, TRIM69. TRIM69-ablation in Cancer cells leads to centrosome scattering and chromosome segregation defects. We identify Serine/threonine-protein kinase 3 (MST2) as a new direct binding partner of TRIM69. TRIM69 redistributes MST2 to the perinuclear Cytoskeleton, promotes its association with Polo-like kinase 1 (PLK1) and stimulates MST2 phosphorylation at S15 (a known PLK1 phosphorylation site that is critical for centrosome disjunction). TRIM69 also promotes microtubule bundling and centrosome segregation that requires PRC1 and DYNEIN. Taken together, we identify TRIM69 as a new proximal regulator of distinct signaling pathways that regulate centrosome dynamics and promote bipolar Mitosis.