Haploinsufficiency of an RB-E2F1-Condensin II Complex Leads to Aberrant Replication and Aneuploidy

Authors

Courtney H. Coschi, Western University
Charles A. Ishak, Western University
David Gallo, University of Toronto Faculty of Medicine
Aren Marshall, Western University
Srikanth Talluri, Western University
Jianxin Wang, Ontario Institute for Cancer Research
Matthew J. Cecchini, Western University
Alison L. Martens, Western University
Vanessa Percy, Western University
Ian Welch, Western University
Paul C. Boutros, Ontario Institute for Cancer Research
Grant W. Brown, University of Toronto Faculty of Medicine
Frederick A. Dick, Western UniversityFollow

Document Type

Article

Publication Date

1-1-2014

Journal

Cancer Discovery

Volume

4

Issue

7

First Page

840

Last Page

853

URL with Digital Object Identifier

10.1158/2159-8290.CD-14-0215

Abstract

Genome instability is a characteristic of malignant cells; however, evidence for its contribution to tumorigenesis has been enigmatic. In this study, we demonstrate that the retinoblastoma protein, E2F1, and Condensin II localize to discrete genomic locations including major satellite repeats at pericentromeres. In the absence of this complex, aberrant replication ensues followed by defective chromosome segregation in mitosis. Surprisingly, loss of even one copy of the retinoblastoma gene reduced recruitment of Condensin II to pericentromeres and caused this phenotype. Using cancer genome data and gene-targeted mice, we demonstrate that mutation of one copy of RB1 is associated with chromosome copy-number variation in cancer. Our study connects DNA replication and chromosome structure defects with aneuploidy through a dosage-sensitive complex at pericentromeric repeats. © 2014 American Association for Cancer Research.