An Aurora kinase A-BOD1L1-PP2A B56 axis promotes chromosome segregation fidelity

  • Cell Rep. 2025 Feb 25;44(2):115317. doi: 10.1016/j.celrep.2025.115317.
Thomas J Kucharski  1 ,  Irma M Vlasac  2 ,  Tatiana Lyalina  3 ,  Martin R Higgs  4 ,  Brock C Christensen  5 ,  Susanne Bechstedt  6 ,  Duane A Compton  7
Affiliations
  • 1. Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7 Canada.
  • 2. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
  • 3. Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7 Canada.
  • 4. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  • 5. Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA; Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA.
  • 6. Department of Anatomy and Cell Biology, McGill University, Montréal, QC H3A 0C7 Canada; Centre de Recherche en Biologie Structurale, McGill University, Montréal, QC H3G 0B1 Canada.
  • 7. Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Electronic address: [email protected].
PMID: 39970043 DOI: 10.1016/j.celrep.2025.115317
Abstract

Cancer cells are often aneuploid and frequently display elevated rates of chromosome mis-segregation, called chromosomal instability (CIN). CIN is caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduce the correction efficiency of erroneous K-MT attachments. UMK57, a chemical agonist of the protein MCAK (mitotic centromere-associated Kinesin), improves chromosome segregation fidelity in CIN Cancer cells by destabilizing K-MT attachments, but cells rapidly develop resistance. To determine the mechanism, we performed unbiased screens, which revealed increased phosphorylation in cells adapted to UMK57 at Aurora Kinase A phosphoacceptor sites on BOD1L1 (protein biorientation defective 1-like-1). BOD1L1 depletion or Aurora Kinase A inhibition eliminated resistance to UMK57. BOD1L1 localizes to spindles/kinetochores during Mitosis, interacts with the PP2A Phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression, and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of Taxol or Aurora Kinase A inhibitor.

Keywords
Aurora; CP: Cancer; CP: Cell biology; kinase; kinetochore; microtubule; mitosis; phosphatase; phosphorylation; spindle.
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