Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

PBRM1 Cooperates with YTHDF2 to Control HIF-1Alpha Protein Translation

Version 1 : Received: 13 April 2021 / Approved: 13 April 2021 / Online: 13 April 2021 (13:24:41 CEST)

A peer-reviewed article of this Preprint also exists.

Shmakova, A.; Frost, M.; Batie, M.; Kenneth, N.S.; Rocha, S. PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation. Cells 2021, 10, 1425. Shmakova, A.; Frost, M.; Batie, M.; Kenneth, N.S.; Rocha, S. PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation. Cells 2021, 10, 1425.

Journal reference: Cells 2021, 10, 1425
DOI: 10.3390/cells10061425

Abstract

PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here we investigated how PBRM1 controls HIF-1alpha activity. We find that PBRM1 is required for HIF-1alpha transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1alpha mRNA translation, as absence of PBRM1 results in reduced activly transalting HIF-1alpha mRNA. Interestingly, we find that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1alpha mRNA is m6A modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1alpha mRNA and reduction of YTHDF2 results in reduced HIF-1alpha protein expression in cells. Our results identify a SWI/SNF independent function for PBRM1, interacting with HIF-1alpha mRNA and the epitranscriptome machinery. Furthermore, our results suggests that the epitranscriptome associated proteins play a role in the control of hypoxia signalling pathways

Subject Areas

PBRM1; HIF-1; SWI/SNF; YTHDF2; m6A; Hypoxia.

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