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



Shmakova, Alena, Frost, Mark, Batie, Michael ORCID: 0000-0002-7508-6641, Kenneth, Niall S ORCID: 0000-0001-8528-1021 and Rocha, Sonia
(2021) PBRM1 Cooperates with YTHDF2 to Control HIF-1 alpha Protein Translation. CELLS, 10 (6). 1425-.

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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-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

Item Type: Article
Uncontrolled Keywords: PBRM1, HIF-1, SWI, SNF, YTHDF2, m6A, hypoxia
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 19 Aug 2021 07:25
Last Modified: 18 Jan 2023 21:33
DOI: 10.3390/cells10061425
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3133942