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• W2073282208 abstract "After DNA damage, cells modulate pre-messenger RNA (pre-mRNA) splicing to induce an anti- or proapoptotic response. In this issue, Muñoz et al., 2009Muñoz M.J. Santangelo M.S.P. Paronetto M.P. de la Mata M. Pelisch F. Boireau S. Glover-Cutter K. Ben-Dov C. Blaustein M. Lozano J.J. et al.Cell. 2009; (this issue)PubMed Google Scholar uncover a cotranscriptional mechanism for activating alternative pre-mRNA splicing after ultraviolet irradiation that depends unexpectedly on hyperphosphorylation of the RNA polymerase II C-terminal domain and decreased rates of transcription elongation. After DNA damage, cells modulate pre-messenger RNA (pre-mRNA) splicing to induce an anti- or proapoptotic response. In this issue, Muñoz et al., 2009Muñoz M.J. Santangelo M.S.P. Paronetto M.P. de la Mata M. Pelisch F. Boireau S. Glover-Cutter K. Ben-Dov C. Blaustein M. Lozano J.J. et al.Cell. 2009; (this issue)PubMed Google Scholar uncover a cotranscriptional mechanism for activating alternative pre-mRNA splicing after ultraviolet irradiation that depends unexpectedly on hyperphosphorylation of the RNA polymerase II C-terminal domain and decreased rates of transcription elongation. In response to a genotoxic insult, normal eukaryotic cells activate the DNA-damage response, which includes programs that mediate DNA repair and apoptosis. For decades, research on the DNA-damage response has focused on signaling kinases, the targets of transcription factors, and transcriptional regulation. More recently, however, it has been shown that alternative pre-messenger RNA (pre-mRNA) splicing is also a target of the DNA-damage response (Katzenberger et al., 2006Katzenberger R.J. Marengo M.S. Wassarman D.A. Mol. Cell. Biol. 2006; 26: 9256-9267Crossref PubMed Scopus (54) Google Scholar, Matsuoka et al., 2007Matsuoka S. Ballif B.A. Smogorzewska A. McDonald 3rd, E.R. Hurov K.E. Luo J. Bakalarski C.E. Zhao Z. Solimini N. Lerenthal Y. et al.Science. 2007; 316: 1160-1166Crossref PubMed Scopus (2211) Google Scholar). In this issue of Cell, Muñoz et al., 2009Muñoz M.J. Santangelo M.S.P. Paronetto M.P. de la Mata M. Pelisch F. Boireau S. Glover-Cutter K. Ben-Dov C. Blaustein M. Lozano J.J. et al.Cell. 2009; (this issue)PubMed Google Scholar describe a new mechanism for genotoxicity-induced alternative splicing that takes a shortcut around the DNA-damage response to target RNA polymerase II (RNAPII), the enzyme that synthesizes pre-mRNA. Muñoz et al. show that ultraviolet (UV) radiation changes the phosphorylation state of the carboxy-terminal repeat domain (CTD) of RNAPII (Figure 1). Using single-locus imaging by fluorescence recovery after photobleaching, the authors conclude that transcription elongation is slower in irradiated cultured human cells. This change in the RNAPII elongation rate seems to affect the RNA available for cotranscriptional splicing (Goldstrohm et al., 2001Goldstrohm A.C. Greenleaf A.L. Garcia-Blanco M.A. Gene. 2001; 277: 31-47Crossref PubMed Scopus (139) Google Scholar). This results in alternative splicing of the BCL-X and CASPASE 9 pre-mRNAs, leading to a proapoptotic response. Alternative splicing of transcripts from these genes appears to occur independently of DNA-damage response signals that are known to play cotranscriptional or posttranscriptional regulatory roles. For example, BRCA1, originally identified as a proto-oncogene in breast cancer, encodes a protein that acts as a critical scaffold for DNA lesion detection and repair. At a DNA lesion, BRCA1 binds directly to the BRCA1-associated RING domain protein (BARD1), a ubiquitin ligase. BARD1 in turn can block RNAPII from interacting with the mRNA polyadenylation factor CstF and also marks RNAPII for degradation (Kim et al., 2006Kim H.S. Li H. Cevher M. Parmelee A. Fonseca D. Kleiman F.E. Lee S.B. Cancer Res. 2006; 66: 4561-4565Crossref PubMed Scopus (30) Google Scholar and references therein) (Figure 1). This could affect steady-state mRNA levels of genes undergoing transcription. However, Muñoz et al. find that neither depleting BARD proteins nor changing the polyadenylation signals on RNA transcripts modulates a UV-induced splicing event. A broadly specific pharmacological block of the DNA-damage response signaling kinases, ATM and ATR, which are known to phosphorylate splicing factors (Matsuoka et al., 2007Matsuoka S. Ballif B.A. Smogorzewska A. McDonald 3rd, E.R. Hurov K.E. Luo J. Bakalarski C.E. Zhao Z. Solimini N. Lerenthal Y. et al.Science. 2007; 316: 1160-1166Crossref PubMed Scopus (2211) Google Scholar), also had no effect. Importantly, Muñoz et al. show that the effect of UV irradiation on alternative splicing is independent of p53, a central regulator of DNA-damage response-induced gene expression. Together, these results suggest the existence of a previously unidentified signaling pathway that modulates alternative splicing in response to DNA damage. The pleiotropic and incomplete effects of the pharmacological inhibition and the small-interfering RNA-mediated depletion of DNA-damage response proteins leave room for alternative explanations. Using a clever chemical genetics approach, however, the investigators were able to demonstrate a role for the RNAPII CTD in the modulation of alternative splicing. They poisoned the activity of endogenous RNAPII in cultured human cells with the toxin α-amanitin and introduced into the same cells α-amanitin-resistant RNAPII that harbors mutations in the repeating CTD heptad protein sequence (YSPTSPS: Y, tyrosine; S, serine; P, proline; T, threonine). Expression of mutant RNAPII in which every serine at positions 2 and 5 in the repeating CTD heptad sequence is replaced by a nonphosphorylatable alanine prevents UV-induced alternative splicing. In contrast, expression of RNAPII mutant proteins in which these serines are replaced by glutamates (which resemble phosphorylated serines) recapitulates UV-induced alternative splicing. These observations indicate that CTD phosphorylation is an important event downstream of UV-induced signaling and that CTD modifications are sufficient to change splicing patterns in living cells. The authors go on to explore the cause and effect of UV-induced CTD phosphorylation. Alternative splicing of the BCL-X and CASPASE 9 transcripts could be perturbed by inhibition of a cyclin-dependent kinase (CDK). CDK dependence would fit well with the observations of Muñoz et al. as CDK9 is known to phosphorylate the CTD of RNAPII upon UV irradiation (Nguyen et al., 2001Nguyen V.T. Kiss T. Michels A.A. Bensaude O. Nature. 2001; 414: 322-325Crossref PubMed Scopus (530) Google Scholar). The consequence of the observed CTD phosphorylation after UV irradiation is, however, new and unexpected. Previous studies indicated that phosphorylation of the CTD heptad repeat serines at positions 2 and 5 is a mark of an elongation-competent RNAPII. Yet, the glutamate phosphomimetic RNAPII mutant proteins exhibit a slower rate of transcription elongation, resulting in local mRNA accumulation similar to that observed for endogenous RNAPII after UV-induced phosphorylation. One possible explanation for this is that CTD phosphorylation is much more than a bulk change in electrostatic charge—rather, it is a context-sensitive code for the differential recruitment of binding partners (Phatnani and Greenleaf, 2006Phatnani H.P. Greenleaf A.L. Genes Dev. 2006; 20: 2922-2936Crossref PubMed Scopus (527) Google Scholar). Mutation or UV-induced phosphorylation of the CTD may disrupt the context necessary for the proper recruitment of transcription elongation factors, resulting in an unexpectedly slow polymerase. It should be noted, however, that the findings in the experiments using fluorescence recovery after photobleaching to determine transcription elongation rates are open to alternative interpretations. Indeed, these experiments show intriguing differences between mutant RNAPII proteins harboring modified CTD sequences and wild-type RNAPII molecules after UV irradiation. Future experiments could explore the role of the lipid messenger ceramide in UV-induced alternative splicing, as UV treatment increases ceramide levels. This lipid can induce dephosphorylation of splicing factors by protein phosphatase 1 (PP1) to regulate the alternative splicing of BCL-X and CASPASE 9 pre-mRNAs (Chalfant et al., 2002Chalfant C.E. Rathman K. Pinkerman R.L. Wood R.E. Obeid L.M. Ogretmen B. Hannun Y.A. J. Biol. Chem. 2002; 277: 12587-12595Crossref PubMed Scopus (282) Google Scholar). Thus, CTD phosphorylation, ceramide, DNA-damage response kinases, and BARD may regulate independent or overlapping pre-mRNA processing programs (Figure 1). The authors also use a splicing-sensitive microarray to identify more UV-induced alternative splicing events, many of which appear to be linked to changes in overall mRNA expression levels. Nonetheless, the direct contribution of CTD phosphorylation to the regulation of global splicing patterns remains unclear. Examining genome-wide splicing changes upon the expression of the glutamate phosphomimetic RNAPII mutant proteins could provide insight into possible global splicing effects. It may be that CTD phosphorylation-induced splicing upregulates a proapoptotic program, whereas other DNA-damage response signals upregulate a pro-repair program. The results of the Muñoz et al. study may have important implications for cancer therapy because the observed splicing effects can be recapitulated by treating cells with the anticancer genotoxin cisplatin. These splicing effects are also independent of the function of p53, which is commonly lost in many human cancers. Thus, understanding how genotoxicity-induced splicing is regulated in the absence of p53 may be critical for designing effective and less toxic cancer therapies. The authors thank C. Webster for improving the figure and A. Greenleaf, D. Wassarman, J. Pearson, C. Bennett, and T. Robinson for comments on the figure and manuscript. DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II ElongationMuñoz et al.CellMay 15, 2009In BriefDNA damage induces apoptosis and many apoptotic genes are regulated via alternative splicing (AS), but little is known about the control mechanisms. Here we show that ultraviolet irradiation (UV) affects cotranscriptional AS in a p53-independent way, through the hyperphosphorylation of RNA polymerase II carboxy-terminal domain (CTD) and a subsequent inhibition of transcriptional elongation, estimated in vivo and in real time. Phosphomimetic CTD mutants not only display lower elongation but also duplicate the UV effect on AS. Full-Text PDF Open Archive" @default.
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• W2073282208 title "Shedding UV Light on Alternative Splicing" @default.
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• W2073282208 doi "https://doi.org/10.1016/j.cell.2009.04.054" @default.
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