Does inactivation of protein phosphatase PP2A contribute to genomic instability in RAS-mutant cancers?

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Protein phosphatase PP2A is a major enzyme involved in different cellular pathways, including cell cycle, metabolism, DNA replication, and transcription. PP2A is frequently inactivated in RAS-mutant cancers, either via mutations in PP2A subunits or by overexpression of PP2A endogenous inhibitors. PP2A inactivation and hyperactivation of RAS signalling are required for malignant transformation of immortalized cells. However, it remains unclear which cellular pathways are affected by PP2A inactivation. RAS mutations promote transcriptional dysregulation and accumulation of R-loops, RNA/DNA hybrids formed during transcription, resulting in replication stress and genomic instability. Interestingly, PP2A activity also regulates transcription and R-loops. We will address whether PP2A inactivation dysregulates transcription and R-loops and thus promotes and/or increases replication stress and genomic instability in RAS-mutant cancer cells. To accomplish this, we will use a PROTAC targeted degradation approach to quickly degrade subunits of PP2A complexes to inactivate or reactivate PP2A activity. We will couple this PROTAC approach with cutting-edge genomics and proteomics and analysis of DNA replication, replication stress, and genomic instability to understand the primary functions of PP2A and the consequences of PP2A inactivation in RAS-mutant cancers. This project will provide important data on PP2A reactivation with PROTACs as a potential strategy to treat RAS-mutant cancers.