The DNA damage response pathway regulates the alternative splicing of the apoptotic mediator Bcl-x.
Alternative splicing often produces effectors with opposite functions in apoptosis. Splicing decisions must therefore be tightly connected to stresses, stimuli, and pathways that control cell survival and cell growth. We have shown previously that PKC signaling prevents the production of proapoptotic Bcl-x(S) to favor the accumulation of the larger antiapoptotic Bcl-x(L) splice variant in 293 cells. Here we show that the genotoxic stress induced by oxaliplatin elicits an ATM-, CHK2-, and p53-dependent splicing switch that favors the production of the proapoptotic Bcl-x(S) variant. This DNA damage-induced splicing shift requires the activity of protein-tyrosine phosphatases. Interestingly, the ATM/CHK2/p53/tyrosine phosphatases pathway activated by oxaliplatin regulates Bcl-x splicing through the same regulatory sequence element (SB1) that receives signals from the PKC pathway. Convergence of the PKC and DNA damage signaling routes may control the abundance of a key splicing repressor because SB1-mediated repression is lost when protein synthesis is impaired but is rescued by blocking proteasome-mediated protein degradation. The SB1 splicing regulatory module therefore receives antagonistic signals from the PKC and the p53-dependent DNA damage response pathways to control the balance of pro- and antiapoptotic Bcl-x splice variants.
Shkreta
Lulzim
L
RNA/RNP Group, Département de Microbiologie et d'Infectiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
Michelle
Laetitia
L
Toutant
Johanne
J
Tremblay
Michel L
ML
Chabot
Benoit
B
D017398:Alternative Splicing / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D004249:DNA Damage; D057809:HEK293 Cells; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*
D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D000077150:Oxaliplatin; D011493:Protein Kinase C; D017027:Protein Tyrosine Phosphatases; D046988:Proteasome Endopeptidase Complex