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Mol Cell Biol. 2019 Jul 29;39(16). pii: e00105-19. doi: 10.1128/MCB.00105-19. Print 2019 Aug 15.

RB1 Deletion in Retinoblastoma Protein Pathway-Disrupted Cells Results in DNA Damage and Cancer Progression.

Author information

1
London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada.
2
Department of Biochemistry, Western University, London, Ontario, Canada.
3
Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
4
Department of Pediatrics, Stanford University, Stanford, California, USA.
5
Department of Genetics, Stanford University, Stanford, California, USA.
6
London Regional Cancer Program, Lawson Health Research Institute, London, Ontario, Canada fdick@uwo.ca.
7
Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada.

Abstract

Proliferative control in cancer cells is frequently disrupted by mutations in the retinoblastoma protein (RB) pathway. Intriguingly, RB1 mutations can arise late in tumorigenesis in cancer cells whose RB pathway is already compromised by another mutation. In this study, we present evidence for increased DNA damage and instability in cancer cells with RB pathway defects when RB1 mutations are induced. We generated isogenic RB1 mutant genotypes with CRISPR/Cas9 in a number of cell lines. Cells with even one mutant copy of RB1 have increased basal levels of DNA damage and increased mitotic errors. Elevated levels of reactive oxygen species as well as impaired homologous recombination repair underlie this DNA damage. When xenografted into immunocompromised mice, RB1 mutant cells exhibit an elevated propensity to seed new tumors in recipient lungs. This study offers evidence that late-arising RB1 mutations can facilitate genome instability and cancer progression that are beyond the preexisting proliferative control deficit.

KEYWORDS:

cell cycle; chemotherapy; haploinsufficiency; metastasis; mitosis

PMID:
31138663
PMCID:
PMC6664603
[Available on 2020-01-29]
DOI:
10.1128/MCB.00105-19

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