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

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 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. 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.

INSTRUMENT(S): LTQ Orbitrap Velos Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Thomas Kucharski

LAB HEAD: Duane Compton

PROVIDER: PXD058824 | Pride | 2025-02-18

REPOSITORIES: pride

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Project description:Accurate chromosome segregation requires that sister kinetochores biorient and attach to microtubules from opposite poles. Kinetochore biorientation relies on the underlying centromeric chromatin, which provides a platform to assemble the kinetochore and to recruit the regulatory factors that ensure the high fidelity of this process. To identify the centromeric chromatin determinants that contribute to chromosome segregation, we performed two complementary unbiased genetic screens using a library of mutants in every residue of histone H3 and H4. In one screen, we identified mutants that lead to increased loss of a non-essential chromosome. In the second screen, we isolated mutants whose viability depends on a key regulator of biorientation, the Aurora B protein kinase. Nine mutations, H3 Q5A, H3 R40A, H3 G44A, H3 R53A, H3 N108A, H3 L109A, H4 K44A, H4 V81A, and H4 Y98A, were common to both screens and exhibited kinetochore biorientation defects. Five of the mutants map near the unstructured nucleosome entry site and their genetic interaction with decreased Ipl1 function can be suppressed by increasing the dosage of the Sgo1 protein. In addition, the composition of purified kinetochores was altered in five of the mutants. Together, this work identifies previously unknown histone residues involved in chromosome segregation and lays the foundation for future studies of the role of the underlying chromatin structure in segregation. Two channel microarrays were used. RNA isolated from a large amount of wt yeast from a single culture was used as a common reference. Two independent cultures were hybridized on two separate microarrays. For the first hybridization the Cy5 (red) labeled cRNA from the deletion mutant is hybridized together with the Cy3 (green) labeled cRNA from the common reference. For the replicate hybridization, the labels are swapped. Each gene is represented twice on the microarray, resulting in four measurements per mutant. Wt cultures were grown parallel to the deletion mutants to assess day-to-day variance.

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	90152.pep.xml	Pepxml
	90152.raw	Raw
	90153.pep.xml	Pepxml
	90153.raw	Raw
	90154.pep.xml	Pepxml

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

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