Projects per year
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.
|Number of pages||16|
|Publication status||Published - 8 Jun 2021|
ASJC Scopus subject areas
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The Interplay Between Oxygen Sensors PHDs and the Cell Cycle (Joint with University of Liverpool)
Fleming, S., Lamond, A. & Swedlow, J.
1/09/17 → 31/08/24
Molecular and Cellular Biology PhD Programme (Ms Alena Shmakova)
1/09/12 → 31/08/16
Mechanisms of Inflammation and Hypoxia-Induced Responses Mediated by HIF and NF-KB in Cancer (Senior Research Fellowship)
Lamond, A. & Rocha, S.
1/08/11 → 1/08/17