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Cancer Discov. 2014 Jul;4(7):840-53. doi: 10.1158/2159-8290.CD-14-0215. Epub 2014 Apr 16.

Haploinsufficiency of an RB-E2F1-Condensin II complex leads to aberrant replication and aneuploidy.

Author information

1
Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
2
Biochemistry, Donnelly Centre, University of Toronto; and.
3
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
4
Authors' Affiliations:London Regional Cancer Program;
5
Veterinary Services, Western University, London; Departments of.
6
Medical Biophysics, and Pharmacology and Toxicology, Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
7
Authors' Affiliations:London Regional Cancer Program; Children's Health Research Institute; Department of Biochemistry, and fdick@uwo.ca.

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.

SIGNIFICANCE:

Genome instability is inherent to most cancers and is the basis for selective killing of cancer cells by genotoxic therapeutics. In this report, we demonstrate that instability can be caused by loss of a single allele of the retinoblastoma gene that prevents proper replication and condensation of pericentromeric chromosomal regions, leading to elevated levels of aneuploidy in cancer.

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PMID:
24740996
DOI:
10.1158/2159-8290.CD-14-0215
[Indexed for MEDLINE]
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