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Poison cassette exon splicing of SRSF6 regulates nuclear speckle dispersal and the response to hypoxia

Authors :
Camila de Oliveira Freitas Machado
Michal Schafranek
Mirko Brüggemann
María Clara Hernández Cañás
Mario Keller
Antonella Di Liddo
Andre Brezski
Nicole Blümel
Benjamin Arnold
Anja Bremm
Ilka Wittig
Nicolas Jaé
François McNicoll
Stefanie Dimmeler
Kathi Zarnack
Michaela Müller-McNicoll
Source :
Nucleic Acids Research. 51:870-890
Publication Year :
2023
Publisher :
Oxford University Press (OUP), 2023.

Abstract

Hypoxia induces massive changes in alternative splicing (AS) to adapt cells to the lack of oxygen. Here, we identify the splicing factor SRSF6 as a key factor in the AS response to hypoxia. The SRSF6 level is strongly reduced in acute hypoxia, which serves a dual purpose: it allows for exon skipping and triggers the dispersal of nuclear speckles. Our data suggest that cells use dispersal of nuclear speckles to reprogram their gene expression during hypoxic adaptation and that SRSF6 plays an important role in cohesion of nuclear speckles. Down-regulation of SRSF6 is achieved through inclusion of a poison cassette exon (PCE) promoted by SRSF4. Removing the PCE 3′ splice site using CRISPR/Cas9 abolishes SRSF6 reduction in hypoxia. Aberrantly high SRSF6 levels in hypoxia attenuate hypoxia-mediated AS and impair dispersal of nuclear speckles. As a consequence, proliferation and genomic instability are increased, while the stress response is suppressed. The SRSF4–PCE–SRSF6 hypoxia axis is active in different cancer types, and high SRSF6 expression in hypoxic tumors correlates with a poor prognosis. We propose that the ultra-conserved PCE of SRSF6 acts as a tumor suppressor and that its inclusion in hypoxia is crucial to reduce SRSF6 levels. This may prevent tumor cells from entering the metastatic route of hypoxia adaptation.

Subjects

Subjects :
Genetics

Details

ISSN :
13624962 and 03051048
Volume :
51
Database :
OpenAIRE
Journal :
Nucleic Acids Research
Accession number :
edsair.doi.dedup.....d0312fcd3683a8dd4ea5d79362d612aa
Full Text :
https://doi.org/10.1093/nar/gkac1225