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Molecular and Cellular Biology, May 2005, p. 3967-3981, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.3967-3981.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

CENP-A Is Required for Accurate Chromosome Segregation and Sustained Kinetochore Association of BubR1

Vinciane Régnier,1,2* Paola Vagnarelli,3 Tatsuo Fukagawa,4 Tatiana Zerjal,1 Elizabeth Burns,1 Didier Trouche,2 William Earnshaw,3 and William Brown5

Department of Biochemistry, Oxford University, South Parks Road, OX1 3QU Oxford, United Kingdom,1 Laboratoire de Biologie Moleculaire Eucaryote, UMR5099, CNRS et Université Paul Sabatier, IFR109, 118, Route de Narbonne, 31062 Toulouse, France,2 Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, United Kingdom,3 National Institute of Genetics, Mishima 411-8540, Japan,4 Institute of Genetics, Nottingham University, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom5

Received 3 February 2005/ Accepted 4 February 2005

CENP-A is an evolutionarily conserved, centromere-specific variant of histone H3 that is thought to play a central role in directing kinetochore assembly and in centromere function. Here, we have analyzed the consequences of disrupting the CENP-A gene in the chicken DT40 cell line. In CENP-A-depleted cells, kinetochore protein assembly is impaired, as indicated by mislocalization of the inner kinetochore proteins CENP-I, CENP-H, and CENP-C as well as the outer components Nuf2/Hec1, Mad2, and CENP-E. However, BubR1 and the inner centromere protein INCENP are efficiently recruited to kinetochores. Following CENP-A depletion, chromosomes are deficient in proper congression on the mitotic spindle and there is a transient delay in prometaphase. CENP-A-depleted cells further proceed through anaphase and cytokinesis with unequal chromosome segregation, suggesting that some kinetochore function remains following substantial depletion of CENP-A. We furthermore demonstrate that CENP-A-depleted cells exhibit a specific defect in maintaining kinetochore localization of the checkpoint protein BubR1 under conditions of checkpoint activation. Our data thus point to a specific role for CENP-A in assembly of kinetochores competent in the maintenance of mitotic checkpoint signaling.

* Corresponding author. Mailing address: Laboratoire de Biologie Moleculaire Eucaryote, UMR5099, CNRS et Université Paul Sabatier, IFR109, 118, Route de Narbonne, 31062 Toulouse, France. Phone: 33 (0) 5 61 33 59 15. Fax: 33 (0) 5 61 33 58 86 E-mail: regnier{at}ibcg.biotoul.fr.

Molecular and Cellular Biology, May 2005, p. 3967-3981, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.3967-3981.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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