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

Alena Shmakova, Mark Frost, Michael Batie, Niall S. Kenneth, Sonia Rocha (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    8 Citations (Scopus)
    63 Downloads (Pure)

    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.

    Original languageEnglish
    Article number1425
    Number of pages16
    JournalCells
    Volume10
    Issue number6
    DOIs
    Publication statusPublished - 8 Jun 2021

    Keywords

    • HIF-1
    • hypoxia
    • m6A
    • PBRM1
    • SWI/SNF
    • YTHDF2

    ASJC Scopus subject areas

    • General Medicine

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