Haploinsufficiency of an RB-E2F1-Condensin II complex causes replication stress and contributes to mesenchymal cancers [γH2AX localization]

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 a complex containing the retinoblastoma protein, E2F1, and Condensin II localizes to major satellite repeats at pericentromeres. In the absence of this complex, this genomic region fails to properly replicate and H2AX phosphorylation at pericentromeric repeats is increased. Our data indicates that these lesions contribute to defective chromosome segregation in the ensuing mitosis. Surprisingly, loss of even one copy of the retinoblastoma gene was sufficient to reduce recruitment of Condensin II to pericentromeres and cause this phenotype. Furthermore, we determined that human RB1 mutation status in cancers of mesenchymal origin correlated with copy number variation, chromosomal gains and losses, as well as chromothriptic rearrangements. Importantly, the magnitude of these chromosomal abnormalities was indistinguishable between RB1+/- and RB1-/- genotypes. Lastly, using gene-targeted mice we determined that mutation of just one copy of the murine Rb1 gene causes sarcomas and lymphomas with increased chromosome copy number variation. Our study connects replication stress with a number of common chromosomal abnormalities in cancer through a dosage sensitive complex present at pericentromeric repeats. γH2AX localization was studied in four different genotypes: Rb+/+, RbΔL/+, RbΔL/ΔL, and Rb-/-. As a control, input from the ChIP experiment was also sequenced. The γH2AX antibody used was supplied by Millipore (catalog number 05-636, and lot number 2116620).

ORGANISM(S): Mus musculus

SUBMITTER: Fred Dick 

PROVIDER: E-GEOD-51558 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress