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Mol Cell. 2014 Mar 20;53(6):993-1004. doi: 10.1016/j.molcel.2014.01.032. Epub 2014 Mar 6.

Suppression of genome instability in pRB-deficient cells by enhancement of chromosome cohesion.

Author information

1
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
2
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: dyson@helix.mgh.harvard.edu.

Abstract

Chromosome instability (CIN), a common feature of solid tumors, promotes tumor evolution and increases drug resistance during therapy. We previously demonstrated that loss of the retinoblastoma protein (pRB) tumor suppressor causes changes in centromere structure and generates CIN. However, the mechanism and significance of this change was unclear. Here, we show that defects in cohesion are key to the pRB loss phenotype. pRB loss alters H4K20 methylation, a prerequisite for efficient establishment of cohesion at centromeres. Changes in cohesin regulation are evident during S phase, where they compromise replication and increase DNA damage. Ultimately, such changes compromise mitotic fidelity following pRB loss. Remarkably, increasing cohesion suppressed all of these phenotypes and dramatically reduced CIN in cancer cells lacking functional pRB. These data explain how loss of pRB undermines genomic integrity. Given the frequent functional inactivation of pRB in cancer, conditions that increase cohesion may provide a general strategy to suppress CIN.

PMID:
24613344
PMCID:
PMC4047977
DOI:
10.1016/j.molcel.2014.01.032
[Indexed for MEDLINE]
Free PMC Article
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