Oncotarget

Research Papers: Chromosome:

Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells

Roshan L. Shrestha, Grace S. Ahn, Mae I. Staples, Kizhakke M. Sathyan, Tatiana S. Karpova, Daniel R. Foltz and Munira A. Basrai _

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Oncotarget. 2017; 8:46781-46800. https://doi.org/10.18632/oncotarget.18108

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Abstract

Roshan L. Shrestha1, Grace S. Ahn1, Mae I. Staples1, Kizhakke M. Sathyan2, Tatiana S. Karpova3, Daniel R. Foltz4 and Munira A. Basrai1

1 Genetics Branch, CCR, NCI, NIH, Bethesda, MD, USA

2 Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA

3 Laboratory of Receptor Biology and Gene Expression, CCR, NCI, NIH, Bethesda, MD, USA

4 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA

Correspondence to:

Munira A. Basrai, email:

Keywords: chromosomal instability, centromeres, cancer, CENP-A, DAXX, Chromosome Section

Received: February 15, 2017 Accepted: May 10, 2017 Published: May 23, 2017

Abstract

Chromosomal instability (CIN) is a hallmark of many cancers and a major contributor to tumorigenesis. Centromere and kinetochore associated proteins such as the evolutionarily conserved centromeric histone H3 variant CENP-A, associate with centromeric DNA for centromere function and chromosomal stability. Stringent regulation of cellular CENP-A levels prevents its mislocalization in yeast and flies to maintain genome stability. CENP-A overexpression and mislocalization are observed in several cancers and reported to be associated with increased invasiveness and poor prognosis. We examined whether there is a direct relationship between mislocalization of overexpressed CENP-A and CIN using HeLa and chromosomally stable diploid RPE1 cell lines as model systems. Our results show that mislocalization of overexpressed CENP-A to chromosome arms leads to chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit. CENP-A overexpressing cells showed altered localization of centromere and kinetochore associated proteins such as CENP-C, CENP-T and Nuf2 leading to weakened native kinetochores as shown by reduced interkinetochore distance and CIN. Importantly, our results show that mislocalization of CENP-A to chromosome arms is one of the major contributors for CIN as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A overexpressing cells. In summary, our results establish that CENP-A overexpression and mislocalization result in a CIN phenotype in human cells. This study provides insights into how overexpression of CENP-A may contribute to CIN in cancers and underscore the importance of understanding the pathways that prevent CENP-A mislocalization for genome stability.


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