Abstract
SummaryRNA binding proteins and signaling components control the production of pro-death and pro-survival splice variants of Bcl-x. DNA damage promoted by oxaliplatin increases the level of pro-apoptotic Bcl-xS in an ATM/CHK2-dependent manner, but how this shift is enforced is not known. Here, we show that in normally growing cells, when the 5′ splice site of Bcl-xS is largely repressed, SRSF10 partially relieves repression and interacts with repressor hnRNP K and stimulatory hnRNP F/H proteins. Oxaliplatin abrogates the interaction of SRSF10 with hnRNP F/H and decreases the association of SRSF10 and hnRNP K with the Bcl-x pre-mRNA. Dephosphorylation of SRSF10 is linked with these changes. A broader analysis reveals that DNA damage co-opts SRSF10 to control splicing decisions in transcripts encoding components involved in DNA repair, cell-cycle control, and apoptosis. DNA damage therefore alters the interactions between splicing regulators to elicit a splicing response that determines cell fate.
Highlights
Programmed cell death or apoptosis plays a critical role during animal development and in maintenance of homeostasis (Clavería et al, 2013)
To investigate which domains are required for the activity of SRSF10 on Bcl-x splicing, we produced a set of HA-SRSF10 variants lacking one or several domains (Figure 1E)
Because SRSF10 interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) F/H and the repressor protein hnRNP K, our results suggest that SRSF10, hnRNP F/H, and hnRNP K are part of a complex that attenuates repression of the 5′ss of Bcl-xS (Figure 4B). hnRNP K-mediated repression likely occurs on the bulk of Bcl-x pre-mRNAs (Figure 4A), whereas the SRSF10mediated anti-repression may be effective only on a small fraction of Bcl-x transcripts
Summary
Programmed cell death or apoptosis plays a critical role during animal development and in maintenance of homeostasis (Clavería et al, 2013). Cancer cells often display resistance to signals that elicit apoptosis, yet many anti-cancer strategies aim to generate sufficient DNA damage to override this barrier and trigger cell death. At least some of these splicing decisions are coordinated by factors involved in cell-cycle control (Moore et al, 2010). DNA damage can reprogram splicing decisions in a variety of cell fate-associated genes including several involved in apoptosis (Dutertre et al, 2014; Naro et al, 2015; Shkreta and Chabot, 2015). DNA damage caused by the topoisomerase inhibitor camptothecin or UV irradiation alters the activity of the Ewing sarcoma protein EWS to affect the alternative splicing of the p53 repressor MDM2 (Dutertre et al, 2010), the FAS/CD95 receptor (Paronetto et al, 2014), and genes involved in DNA repair (Paronetto et al, 2011). DNA damage triggers the formation of a complex between BRCA1 and splicing factors that localizes at DNA repair genes to stimulate co-transcriptional splicing (Savage et al, 2014)
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