PI3K-AKT activation determines oncogenic RAS-induced hypertranscription and replication stress [ChrRNAseq]

RAS oncogenes promote RNA polymerase activity and hypertranscription for cell growth and proliferation, which can the lead to TRCs. Here, we investigated hypertranscription and replication stress induced by the HRAS and KRAS oncogenes, and their downstream signalling through the MAPK and PI3K pathways.

We show that HRAS causes more TRCs than KRAS because HRAS specifically hyperactivates the PI3K-AKT signalling pathway. MAPK signalling is insufficient to cause hypertranscription and TRCs, which require PI3K activity. PI3K hyperactivation was associated with increased E2F and MYC transcription programmes, increased S phase entry, increased nascent transcription of genes encoding ribosome biogenesis factors and expression of small nucleolar RNAs (snoRNAs).