2. Academic Validation
  3. An Aurora kinase A-BOD1L1-PP2A B56 axis promotes chromosome segregation fidelity

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

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.

Figures
Products