Abstract
ABSTRACT Hypertranscription and transcription-replication conflicts (TRCs) are frequent features of cancer cells. RAS oncogenes promote hypertranscription to allow cell growth and proliferation, which can the lead to TRCs. Here, we report that hyperactivation of the PI3K-AKT signalling pathway is required for TRCs induced by RAS oncogenes. Oncogenic HRAS causes more TRCs than oncogenic KRAS or BRAF, because HRAS hyperactivates PI3K. PI3K hyperactivation is associated with in glycogen synthase kinase-3β (GSK3β) inhibition, increased E2F and MYC transcription programmes, increased nascent transcription of ribosome biogenesis genes and small nucleolar RNAs (snoRNA) expression. Small molecule inhibition of PI3K signalling prevents RAS-induced replication stress, and small molecule PI3K activation promotes replication stress. RAS-induced TRCs require a cooperation of MAPK and Pi3K signalling, S phase entry and hypertranscription. Our findings suggest a mechanistic explanation for replication stress variability between RAS activation models and identify PI3K pathway activation as a potential new determinant of TRCs in cancer.
Full text
1,222 characters
· extracted from
oa-doi-fallback
· click to expand
ABSTRACT
Hypertranscription and transcription-replication conflicts (TRCs) are frequent features of cancer cells. RAS oncogenes promote hypertranscription to allow cell growth and proliferation, which can the lead to TRCs. Here, we report that hyperactivation of the PI3K-AKT signalling pathway is required for TRCs induced by RAS oncogenes. Oncogenic HRAS causes more TRCs than oncogenic KRAS or BRAF, because HRAS hyperactivates PI3K. PI3K hyperactivation is associated with in glycogen synthase kinase-3β (GSK3β) inhibition, increased E2F and MYC transcription programmes, increased nascent transcription of ribosome biogenesis genes and small nucleolar RNAs (snoRNA) expression. Small molecule inhibition of PI3K signalling prevents RAS-induced replication stress, and small molecule PI3K activation promotes replication stress. RAS-induced TRCs require a cooperation of MAPK and Pi3K signalling, S phase entry and hypertranscription. Our findings suggest a mechanistic explanation for replication stress variability between RAS activation models and identify PI3K pathway activation as a potential new determinant of TRCs in cancer.
Competing Interest Statement
E.P. has a consulting contract with Storm Therapeutics.
Text is read by the "Ask this paper" AI Q&A widget below.
Extraction quality varies by source — PMC NXML preserves structure
cleanly, OA-HTML may include some navigation residue, and OA-PDF can
have broken hyphenation. The publisher copy
(via DOI)
is the canonical version.