Oncotarget

Research Papers:

Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability

Maxim Pilyugin _, Pierre-Alain André, Magdalena Ratajska, Alina Kuzniacka, Janusz Limon, Benjamin B. Tournier, Julien Colas, Geoff Laurent and Irmgard Irminger-Finger

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:9339-9353. https://doi.org/10.18632/oncotarget.14068

Metrics: PDF 1374 views  |   HTML 2016 views  |   ?  


Abstract

Maxim Pilyugin1, Pierre-Alain André1, Magdalena Ratajska2,4, Alina Kuzniacka2, Janusz Limon2, Benjamin B. Tournier3, Julien Colas1, Geoff Laurent4, Irmgard Irminger-Finger1,4,5

1Department of Gynecology and Obstetrics Geneva University Hospitals, Geneva, Switzerland

2Department of Biology and Genetics, Medical University of Gdansk, Poland

3Department of Neuropsychiatry, Vulnerability Biomarkers Unit, University Hospital of Geneva, Geneva, Switzerland

4Centre for Cell Therapy and Regenerative Medicine, University of Western Australia and Institute of Respiratory Health, Nedlands, Australia

5Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

Correspondence to:

Maxm Pilyugin, email: maxim.pilyugin@unige.ch

Keywords: BARD1, alternative splicing, telomere alteration, shelterin, genome permutator

Received: October 20, 2016     Accepted: December 15, 2016     Published: December 21, 2016

ABSTRACT

Previous reports have shown that expression of BARD1δ, a deletion-bearing isoform of BARD1, correlates with tumor aggressiveness and progression. We show that expression of BARD1δ induces cell cycle arrest in vitro and in vivo in non-malignant cells. We investigated the mechanism that leads to proliferation arrest and found that BARD1δ overexpression induced mitotic arrest with chromosome and telomere aberrations in cell cultures, in transgenic mice, and in cells from human breast and ovarian cancer patients with BARD1 mutations. BARD1δ binds more efficiently than BARD1 to telomere binding proteins and causes their depletion from telomeres, leading to telomere and chromosomal instability. While this induces cell cycle arrest, cancer cells lacking G2/M checkpoint controls might continue to proliferate despite the BARD1δ-induced chromosomal instability. These features of BARD1δ may make it a genome permutator and a driver of continuous uncontrolled proliferation of cancer cells.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 14068