Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism.
Wragg, Joseph W White, Paige-Louise Hadzhiev, Yavor Wanigasooriya, Kasun Stodolna, Agata Tee, Louise Barros-Silva, Joao D Beggs, Andrew D Müller, Ferenc
Wragg, Joseph W
White, Paige-Louise
Hadzhiev, Yavor
Wanigasooriya, Kasun
Stodolna, Agata
Tee, Louise
Barros-Silva, Joao D
Beggs, Andrew D
Müller, Ferenc
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2023-11-23
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Abstract
development. However, little is known about the role of the core promoter in defining transcript identity and post-transcriptional fates, a potentially crucial layer of transcriptional regulation in cancer. In this study, we use CAGE-seq analysis to uncover widespread use of dual-initiation promoters in which non-canonical, first-base-cytosine (C) transcription initiation occurs alongside first-base-purine initiation across 59 human cancers and healthy tissues. C-initiation is often followed by a 5' terminal oligopyrimidine (5'TOP) sequence, dramatically increasing the range of genes potentially subjected to 5'TOP-associated post-transcriptional regulation. We show selective, dynamic switching between purine and C-initiation site usage, indicating transcription initiation-level regulation in cancers. We additionally detail global metabolic changes in C-initiation transcripts that mark differentiation status, proliferative capacity, radiosensitivity, and response to irradiation and to PI3K-Akt-mTOR and DNA damage pathway-targeted radiosensitization therapies in colorectal cancer organoids and cancer cell lines and tissues.
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Wragg JW, White PL, Hadzhiev Y, Wanigasooriya K, Stodolna A, Tee L, Barros-Silva JD, Beggs AD, Müller F. Intra-promoter switch of transcription initiation sites in proliferation signaling-dependent RNA metabolism. Nat Struct Mol Biol. 2023 Dec;30(12):1970-1984. doi: 10.1038/s41594-023-01156-8. Epub 2023 Nov 23.
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