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.

The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the SerRich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting. Cell Death and Differentiation (2008) 15, 1815-1823 doi:10.1038/cdd.2008 published online 19 September 2008 Pre-mRNA splicing is an essential step for the expression of most genes in higher eukaryotic cells. This process has emerged as an important mechanism of genetic diversity as about 74% of human genes undergo alternative splicing, leading to the production of various protein isoforms. 1 SC35 belongs to the serine/arginine-rich (SR) protein family, one of the most important class of splicing regulators. Members of the SR family have a modular structure consisting of one or two copies of an N-terminal RRM (RNA-recognition motif) followed by a C terminus rich in serine and arginine residues known as the RS domain. They act at multiple steps of spliceosome assembly and participate in both constitutive and alternative splicing. 2 Together with most of the other splicing factors, SR proteins localize to nuclear subregions termed nuclear speckles. 3 Extensive serine phosphorylation of the RS domain has an important function in the regulation of both the localization and the activities of SR proteins. 4 Although the splicing functions of SR proteins have been well documented in vitro, their roles and physiological targets in vivo are less well known. However, based on gene targeting experiments demonstrating that they are required for cell viability and/or animal development, SR proteins undoubtedly control essential biological functions.Apoptosis is one of the cellular processes in which alternative splicing has an important regulatory function. Indeed, a remarkable number of transcripts that encode proteins involved in the apoptotic pathway are subjected to alternative splicing. This usually drives the expression of proteins with opposite functions, either pro-or anti-apoptotic. 5 Interestingly, changes in SR protein phosphorylation have been observed upon apoptotic stimulation following activation of the Fas receptor. 6 In addition, in vitro overexpression experiments have suggested a potential role for ...