title: SRSF10 Connects DNA Damage to the Alternative Splicing of Transcripts Encoding Apoptosis, Cell-Cycle Control, and DNA Repair Factors.
abstract: RNA 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.
authors.affiliation: Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Lulzim
authors.initials: L
authors.lastname: Shkreta
authors.affiliation: Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Toutant
authors.affiliation: Laboratory of Functional Genomics, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Durand
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Manley
authors.affiliation: Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada. Electronic address: benoit.chabot@usherbrooke.ca.
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D012322:RNA Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009944:Organoplatinum Compounds; D012322:RNA Precursors; D012333:RNA, Messenger; D012097:Repressor Proteins; C115188:SRSF10 protein, human; D051020:bcl-X Protein; D000077150:Oxaliplatin; D000068103:Serine-Arginine Splicing Factors
keywords: DNA damage response; DNA repair; RNA binding proteins; SR proteins; alternative splicing; apoptosis; cell cycle; cell fate; hnRNP proteins; oxaliplatin; phosphorylation; splicing