Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors

Autor:	Katrina M. Lappin, Eliana M. Barros, Satpal S. Jhujh, Gareth W. Irwin, Hayley McMillan, Fabio G. Liberante, Cheryl Latimer, Melissa J. La Bonte, Ken I. Mills, D. Paul Harkin, Grant S. Stewart, Kienan I. Savage
Rok vydání:	2022
Předmět:	DNA Replication Cancer Research Poly(ADP-ribose) Polymerase Inhibitors Phosphoproteins Article Phenotype SDG 3 - Good Health and Well-being Oncology Neoplasms Mutation Humans RNA Splicing Factors Synthetic Lethal Mutations
Zdroj:	Lappin, K M, Barros, E M, Jhujh, S S, Irwin, G W, McMillan, H, Liberante, F G, Latimer, C, LaBonte, M J, Mills, K I, Harkin, D P, Stewart, G S & Savage, K I 2022, ' Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors ', Cancer Research, vol. 82, no. 5, pp. 819-830 . https://doi.org/10.1158/0008-5472.CAN-21-1843 Cancer Res
ISSN:	1538-7445 0008-5472
DOI:	10.1158/0008-5472.can-21-1843
Popis:	Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response to DNA damage. Here, we demonstrate that depletion of SF3B1 specifically compromises homologous recombination (HR) and is epistatic with loss of BRCA1. More importantly, the most prevalent cancer-associated mutation in SF3B1, K700E, also affects HR efficiency and as a consequence, increases the cellular sensitivity to ionizing radiation and a variety of chemotherapeutic agents, including PARP inhibitors. In addition, the SF3B1 K700E mutation induced unscheduled R-loop formation, replication fork stalling, increased fork degradation, and defective replication fork restart. Taken together, these data suggest that tumor-associated mutations in SF3B1 induce a BRCA-like cellular phenotype that confers synthetic lethality to DNA-damaging agents and PARP inhibitors, which can be exploited therapeutically. Significance: The cancer-associated SF3B1K700E mutation induces DNA damage via generation of genotoxic R-loops and stalled replication forks, defective homologous recombination, and increased replication fork degradation, which can be targeted with PARP inhibitors.
Databáze:	OpenAIRE
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