Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin

SRSF2 is a serine/arginine‐rich protein belonging to the family of SR proteins that are crucial regulators of constitutive and alternative pre‐mRNA splicing. Although it is well known that phosphorylation inside RS domain controls activity of SR proteins, other post‐translational modifications regul...

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Bibliographic Details
Published in:	The EMBO journal Vol. 30; no. 3; pp. 510 - 523
Main Authors:	Edmond, Valerie, Moysan, Elodie, Khochbin, Saadi, Matthias, Patrick, Brambilla, Christian, Brambilla, Elisabeth, Gazzeri, Sylvie, Eymin, Beatrice
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 02.02.2011 Nature Publishing Group UK Springer Nature B.V Nature Publishing Group
Subjects:	Acetylation Alternative Splicing - drug effects Blotting, Western Caspase 8 - genetics Caspase 8 - metabolism Cell Cycle - drug effects Cell Cycle - physiology Cell Differentiation - drug effects Cell Differentiation - physiology Cell Line, Tumor Cisplatin - pharmacology DNA Primers - genetics Histone Acetyltransferases - metabolism Histone Deacetylase 6 Histone Deacetylases - metabolism Humans Immunoprecipitation Lysine - metabolism Lysine Acetyltransferase 5 Molecular biology Nuclear Proteins - metabolism Oligonucleotides - genetics Phosphorylation Proteases Proteins Reverse Transcriptase Polymerase Chain Reaction Ribonucleoproteins - metabolism RNA, Small Interfering - genetics RNA-protein interactions Serine-Arginine Splicing Factors Signal Transduction - genetics Signal Transduction - physiology SRPK SRSF2 Tip60 Transfection Translocation acetylation SRSF2 Tip60 SRPK phosphorylation
ISSN:	0261-4189, 1460-2075, 1460-2075
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Summary:	SRSF2 is a serine/arginine‐rich protein belonging to the family of SR proteins that are crucial regulators of constitutive and alternative pre‐mRNA splicing. Although it is well known that phosphorylation inside RS domain controls activity of SR proteins, other post‐translational modifications regulating SRSF2 functions have not been described to date. In this study, we provide the first evidence that the acetyltransferase Tip60 acetylates SRSF2 on its lysine 52 residue inside the RNA recognition motif, and promotes its proteasomal degradation. We also demonstrate that the deacetylase HDAC6 counters this acetylation and acts as a positive regulator of SRSF2 protein level. In addition, we show that Tip60 downregulates SRSF2 phosphorylation by inhibiting the nuclear translocation of both SRPK1 and SRPK2 kinases. Finally, we demonstrate that this acetylation/phosphorylation signalling network controls SRSF2 accumulation as well as caspase‐8 pre‐mRNA splicing in response to cisplatin and determines whether cells undergo apoptosis or G 2 /M cell cycle arrest. Taken together, these results unravel lysine acetylation as a crucial post‐translational modification regulating SRSF2 protein level and activity in response to genotoxic stress. SR family proteins regulate alternative splicing. In this study, the Tip60 acetyltransferase regulates splicing by directly acetylating the splicing factor SRSF2, leading to its proteasomal degradation, and indirectly by relocalising the SRPK1/2 kinase, thereby reducing the phosphorylation levels of SRSF2.
Bibliography:	Supplementary dataReview Process File istex:DEBB612A5A529D580A582EFA24F1947D44615AC3 ArticleID:EMBJ2010333 ark:/67375/WNG-5WZQR1P0-D ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.1038/emboj.2010.333