ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II

Seina Ohe, Yuji Kubota, Kiyoshi Yamaguchi, Yusuke Takagi, Junichiro Nashimoto, Hiroko Kozuka-Hata, Masaaki Oyama, Yoichi Furukawa and Mutsuhiro Takekawa ()
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Seina Ohe: The University of Tokyo
Yuji Kubota: The University of Tokyo
Kiyoshi Yamaguchi: The University of Tokyo
Yusuke Takagi: The University of Tokyo
Junichiro Nashimoto: The University of Tokyo
Hiroko Kozuka-Hata: The University of Tokyo
Masaaki Oyama: The University of Tokyo
Yoichi Furukawa: The University of Tokyo
Mutsuhiro Takekawa: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Growth factor-induced, ERK-mediated induction of immediate-early genes (IEGs) is crucial for cell growth and tumorigenesis. Although IEG expression is mainly regulated at the level of transcription elongation by RNA polymerase-II (Pol-II) promoter-proximal pausing and its release, the role of ERK in this process remains unknown. Here, we identified negative elongation factor (NELF)-A as an ERK substrate. Upon growth factor stimulation, ERK phosphorylates NELF-A, which dissociates NELF from paused Pol-II at the promoter-proximal regions of IEGs, allowing Pol-II to resume elongation and produce full-length transcripts. Furthermore, we found that in cancer cells, PP2A efficiently dephosphorylates NELF-A, thereby preventing aberrant IEG expression induced by ERK-activating oncogenes. However, when PP2A inhibitor proteins are overexpressed, as is frequently observed in cancers, decreased PP2A activity combined with oncogene-mediated ERK activation conspire to induce NELF-A phosphorylation and IEG upregulation, resulting in tumor progression. Our data delineate previously unexplored roles of ERK and PP2A inhibitor proteins in carcinogenesis.

Date: 2022
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DOI: 10.1038/s41467-022-35230-4

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