RB1 deletion in retinoblastoma protein pathway-disrupted cells results in DNA damage and cancer progression
| Autor: | Frederick A. Dick, Megan C. DeWeerd, Aren E. Marshall, Daniel Thompsen Passos, Christopher J. Howlett, Michael V. Roes, Andrea C. Chaikovsky, Julien Sage |
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| Rok vydání: | 2019 |
| Předmět: |
Genome instability
DNA damage Mitosis Haploinsufficiency Cell cycle medicine.disease_cause Metastasis 03 medical and health sciences 0302 clinical medicine medicine Chemotherapy Molecular Biology 030304 developmental biology 0303 health sciences Mutation biology Retinoblastoma protein Cell Biology eye diseases 3. Good health 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Homologous recombination Carcinogenesis Research Article |
| Zdroj: | Paediatrics Publications |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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