title: Haploinsufficiency of an RB-E2F1-Condensin II complex leads to aberrant replication and aneuploidy.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
authors.forename: Courtney H
authors.initials: CH
authors.lastname: Coschi
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Ishak
authors.affiliation: Biochemistry, Donnelly Centre, University of Toronto; and.
authors.forename: David
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
authors.forename: Aren
authors.initials: A
authors.lastname: Marshall
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Talluri
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Department of Biochemistry, and.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Martens
authors.affiliation: Authors' Affiliations:London Regional Cancer Program;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Percy
authors.affiliation: Veterinary Services, Western University, London; Departments of.
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.affiliation: Medical Biophysics, and Pharmacology and Toxicology, Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Biochemistry, Donnelly Centre, University of Toronto; and.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
authors.affiliation: Authors' Affiliations:London Regional Cancer Program; Children's Health Research Institute; Department of Biochemistry, and fdick@uwo.ca.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002503:Centromere / Q000378:metabolism; D056915:DNA Copy Number Variations; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D046912:Multiprotein Complexes; D016160:Retinoblastoma Protein; C108312:condensin complexes; D000251:Adenosine Triphosphatases