Abstract 235: Global RNA Splicing and Regulation in Cardiac Maturation and Diseases

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
CHEN GAO ◽  
Vincent Ren ◽  
Jae-Hyung Lee ◽  
Xinshu (Grace) Xiao ◽  
Jau-nian Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Alternative Splicing ◽  
Cardiac Function ◽  
Rna Splicing ◽  
Cardiac Development ◽  
Mrna Splicing ◽  
Pcr Analysis ◽  
Mouse Heart ◽  
Global Pattern ◽  
Alternative Mrna Splicing

Background: The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is also implicated in many human diseases including cancer. However, the global pattern of alternative mRNA splicing during cardiac development and diseases is unknown, and the regulatory mechanisms remain unexplored. Methods and Results: Using deep RNA-Sequencing, we have identified global alternative splicing changes associated with both cardiac development and pathological remodeling in mouse heart following pressure-overload induced heart failure. The alternative RNA splicing events observed in failing hearts mimics the profile in fetal hearts, suggesting a fetal-like RNA splicing program induced in diseased hearts. Using RNA-Seq database and real-time PCR analysis, we examined the expression profile of a large number of known alternative splicing regulators. Among them, we identified Fox1 as a significantly induced regulator during cardiac development in zebrafish, mouse and human, and down-regulated in both mouse and human failing hearts. Morpholino mediated Fox1 knockdown in zebrafish embryos led to lethal phenotype associated with reduced cardiac function and defects in chamber specificity. This phenotype could be rescued by re-expressing both zebrafish and mouse Fox1 gene, suggesting a highly conserved cardiac function of Fox1 for normal cardiac development and function in vertebrates. Conclusion: Our study provided the first comprehensive analysis of mRNA splicing regulation in heart during post-natal development and heart failure, and identified Fox1 as a key regulator for alternative RNA splicing in heart. This study expands our current understanding to the complexity of cardiac transcriptome, and reveals the functional importance of RNA-splicing in cardiac development and diseases.

Abstract 124: Fetal-Like RNA Splicing Remodeling in Failing Heart Revealed by Total Transcriptome Analysis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Chen Gao ◽  
Vincent Ren ◽  
Grace (Xinshu) Xiao ◽  
Jaunian Chen ◽  
Yibin Wang
Keyword(s):  
Alternative Splicing ◽  
Rna Splicing ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Expression Profiles ◽  
Mrna Splicing ◽  
Mouse Heart ◽  
Failing Heart ◽  
Splicing Regulators ◽  
A Genome

The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is also implicated in many human diseases including cancer. However, little knowledge is available about the scope of alternative splicing at whole genome level in heart diseases and even less about the mechanisms underlying the regulation of mRNA splicing in response to pathological injury in heart. Using a genome-wide RNA-Seq analysis, we have identified global alternative splicing changes associated with both development and pathological remodeling in mouse heart. Most significantly, the alternative RNA splicing events observed in failing heart mimicked the splicing profile in fetal hearts, suggesting a fetal like RNA splicing remodeling in failing hearts. After examining the expression profiles of splicing regulators in neonatal, normal adult, and failing adult hearts, Fox-1 was identified as one to be significantly down regulated in the failing and fetal hearts. Morpholino mediated Fox-1 knock-down in zebrafish embryos led to lethal phenotype associated with impaired cardiac development and function. This phenotype could be rescued by re-expressing both zebrafish and mouse Fox1 gene. Therefore, our established functional significance of Fox1 mediated RNA alternative splicing serves as a key molecular player in transcriptome remodeling during cardiac development and pathology.

Abstract 240: Differential Impact of RBFox Family Proteins in Adult Murine Heart

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Chen Gao ◽  
Shuxun Ren ◽  
Yibin Wang
Keyword(s):  
Heart Failure ◽  
Alternative Splicing ◽  
Rna Splicing ◽  
Adult Mouse ◽  
Regulatory Elements ◽  
Global Changes ◽  
Mouse Heart ◽  
Cardiac Physiology ◽  
Differential Impact ◽  
Adult Heart

Background: The complexity of cardiac transcriptome and proteome is significantly contributed by alternative splicing of mRNA. Alternative splicing is regulated by the cis-regulatory elements located in pre-mRNA together with the trans-activating factors guiding the assembling and function of the spliceosome. In our earlier study, we have observed global changes of alternative splicing events during pressure-overload induced heart failure, and identified RBFox1 as a key regulator for cardiac RNA splicing regulation during postnatal development and pathological remodeling. Both RBFox1 and RBFox2 are highly enriched in cardiomyocytes, and their expression are both significantly repressed in response to pathological stress. Loss-of-function studies for RBFox1 and RBFox2 are achieved using cardiac specific but constitutively active Cre. Therefore, the isoform specific contribution of RBFox1 vs. RBFox2 in maintaining cardiac physiology and homeostasis in adult heart is unknown. Methods and Results: We generated mouse models of cardiac specific and inducible knockout of RBFox1 and RBFox2 individually in adult hearts by breeding the individual floxed alleles with the αMHC-Mer-Cre-Mer mice. At baseline, inactivating RBFox1 in adult heart caused a slight but significant decrease of cardiac function without activating hypertrophy gene expression. However, following myocardial infarction, the RBFox1 deficient hearts showed enhanced global fibrosis in non-infarcted areas comparing to the control animals. In contrast, inactivating RBFox2 in adult mouse heart caused overt heart failure associated with chamber dilation without external stress as early as 2 weeks post tamoxifen administration. Conclusion: We have identified differential impact of RBFox1 and RBFox2 deficiency in adult mouse heart. Our in vivo study illustrate the functional importance of the RBFox family RNA splicing regulators in normal physiology of adult heart, and support the pathogenic contribution of loss of RBFox expression to heart failure. Further analysis focusing on the underlying molecular mechanisms for their differential impact would yield new insights on transcriptome regulation and complexity in cardiac physiology and diseases.

Abstract 15: Global RNA Splicing Regulation in Cardiac Maturation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Chen Gao ◽  
Shuxun Ren ◽  
Jae-Hyung Lee ◽  
Yun-Hua Esther Hsiao ◽  
Xinshu (Grace) Xiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Sequencing ◽  
Rna Splicing ◽  
Mrna Splicing ◽  
Splicing Regulation ◽  
Sequencing Analysis ◽  
Cell Based Therapy ◽  
Alternative Mrna Splicing ◽  
Cardiac Maturation

Background: The complexity of transcriptome and proteome is contributed by alternative splicing of mRNA. Altered mRNA splicing is implicated in both development and disease. However, the change of alternative mRNA splicing during cardiomyocytes maturation is unknown, and the regulatory mechanisms remain unexplored. Methods and Results: Using deep RNA-Sequencing, we identified global alternative splicing changes associated with both cardiac development and pathological remodeling in mouse heart. Further, we identified a highly conserved splicing regulator-RBFox1 to be significantly induced during zebrafish, mouse and human cardiac maturation. RBFox1 expression was also detected in cardiomyocytes derived from both mouse and human embryonic stem cells but at much lower levels comparing to adult heart. In zebrafish embryos, inactivation of RBFox1 caused cardiomyocyte maturation defects. Expression of RBFox1 in cultured neonatal cardiomyocytes was sufficient to promote maturation by reducing fetal marker gene expression while increasing calcium handling gene expression including RyR and promoting sarcomere organization. Deep RNA-Sequencing analysis showed that RBFox1 expression promoted alternative splicing in genes involved in calcium cycling, blood vessel development and muscle contraction. Finally, we identified a highly conserved mutually exclusive alternative splicing event of transcription factor MEF2 to be a direct downstream target of RBFox1. Expression of individual MEF2 splicing variants led to different cardiac developmental phenotypes in zebrafish, indicating their different transcriptional activities. Conclusion: Our study provided the first comprehensive analysis of mRNA splicing regulation in heart during post-natal development and heart failure, and identified RBFox1 as a key regulator for alternative RNA splicing during cardiomyocytes maturation. Further exploration of RBFox1 mediated RNA splicing regulation in heart may yield novel insight to the underlying mechanisms of cardiac maturation and new approach to improve cell based therapy for heart diseases.

scholarly journals Identification of a Novel Estrogen Receptor-α Variant and Its Upstream Splicing Regulator

2010 ◽  
Vol 24 (5) ◽  
pp. 914-922 ◽  
Author(s):  
Kazufumi Ohshiro ◽  
Prakriti Mudvari ◽  
Qing-chang Meng ◽  
Suresh K. Rayala ◽  
Aysegul A. Sahin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Alternative Splicing ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Α ◽  
Mrna Splicing ◽  
Human Breast ◽  
Alternative Mrna Splicing

Abstract Alternative splicing of precursor mRNA is a fundamental mechanism to generate multiple proteins from a single gene. Although constitutive and alternative mRNA splicing is temporally and spatially regulated, deregulation of mRNA splicing could cause development, progression, and metastasis of tumors. Through yeast two-hybrid screening of a human breast cDNA library using estrogen receptor-α (ERα) as bait, we identified a novel nuclear receptor box containing full-length protein, nuclear protein E3-3 (NPE3-3). Our results revealed that NPE3-3 associates with not only ERα but also with splicing factors, serine/arginine-rich protein (SRp)-30c, SRp40, and splicing factor SC-35, suggesting that NPE3-3 is likely to be involved in regulation of mRNA splicing. Accordingly, transient expression of NPE3-3 in cells resulted in expected splicing of the CD44 control minigene. We also discovered that NPE3-3-overexpressing clones produced a novel, previously unrecognized, alternatively spliced variant of ERα (termed ERαV), which had a molecular size of 37 kDa composed of only exons 1, 2, 7, and 8. ERαV was expressed and sequestered in the cytoplasm in MCF-7 cells stably overexpressing NPE3-3, suggesting its involvement in nongenomic hormone signaling. NPE3-3 clones exhibited up-regulation of ERK1/2 signaling, cyclin D1, and cathepsin D and enhanced tumor cell proliferation, migration, and tumorigenicity. Moreover, direct expression of the ERαV in breast cancer cells stimulated ERK1/2 up-regulation and cyclin D1 expression. We found that ERαV physically interacted with MAPK kinase (MEK)-1/2, and thus, an ERαV and MEK1/2 complex could lead to the activation of the ERK1/2 pathway. Interestingly, NPE3-3 was up-regulated in human breast tumors. These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERα is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells.

scholarly journals MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1818
Author(s):  
Rahaba Marima ◽  
Flavia Zita Francies ◽  
Rodney Hull ◽  
Thulo Molefi ◽  
Meryl Oyomno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Alternative Splicing ◽  
Mirna Expression ◽  
Drug Targets ◽  
Mrna Splicing ◽  
Cancer Drug ◽  
Aberrant Splicing ◽  
Cancer Drug Resistance ◽  
Alternative Mrna Splicing

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3′UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3′UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.

Abstract 10: Antifibrotic Effect of CCN5 in a Murine Model of Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dongtak Jeong ◽  
Changwon Kho ◽  
Ahyoung Lee ◽  
Woo Jin Park ◽  
Roger Hajjar
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Heart Function ◽  
Pcr Analysis ◽  
Tgf Beta ◽  
Human Heart Failure ◽  
Ccn Family

CCN family members are matricellular proteins with diverse roles in cell function. Recently, we showed that the differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. Since it is reported that an underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart, we aimed to evaluate the role of CCN5 on cardiac fibrosis and function by the gene delivery using the cardiotropic AAV9 vector. We generated pressure-overload heart failure models in mouse by TAC operation. After 8-10 weeks of TAC on mice, HF was confirmed by Echocardiography. In those HF mice, AAV9-GFP (control) and AAV9-CCN5 were addressed by IV. Two more months later, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of CCN5, several types of collagen and conventional TGF-beta signaling related genes were evaluated by western blot and quantitative real time PCR analysis. First, we were able to achieve about 4-5 fold increase of CCN5 expression by AAV9-CCN5 injection without any change in heart function. Second, CCN5 expression level in blood was not significantly altered after AAV9-CCN5 gene transfer because it may be the result of the cardiac tropism of the vector used. The HF model by TAC surgery was confirmed with echocardiography (FS (%)). Overall average FS (%) in HF was 41.87+/− 5.27 (n=16) and in non-surgery control mice was 58.39 +/− 2.06(n=4). After AAV9 injection, cardiac function of CCN5 injected mice was sustained but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (24.29+/− 9.11) vs AAV-CCN5 (42.66 +/− 4.73)). Third, western blot analysis showed that the downstream effectors, namely TGF-beta signaling pathways were significantly down-regulated in CCN5 injected mice. In addition, fibrotic area of the heart was tremendously reduced. Finally, CCN5 expression is significantly decreased in human heart failure patients compared to those in nonfailing donors. Taken together our data would indicate that CCN5 may be a promising therapeutic target to reduce cardiac fibrosis.

Abstract 519: Talin is Required for Normal Adult Heart Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshitake Cho ◽  
Ruixia Li ◽  
Ana M Manso ◽  
Robert S Ross
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Development ◽  
Heart Function ◽  
Left Ventricular ◽  
Mass Spectrometry Analysis ◽  
Adult Heart ◽  
Spectrometry Analysis ◽  
Functional Changes

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.

scholarly journals Recombinant Soluble Corin Improves Cardiac Function in Mouse Models of Heart Failure

2021 ◽  
Author(s):  
Yayan Niu ◽  
Shengnan Zhang ◽  
Xiabing Gu ◽  
Tiantian Zhou ◽  
Feng Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Mouse Models ◽  
Soluble Form ◽  
Pharmacokinetic Studies ◽  
Mouse Heart ◽  
Coronary Artery Ligation ◽  
Cardiac Morphology ◽  
Failure Models ◽  
And Function

Background Corin is a transmembrane protease that activates ANP and BNP (atrial and B‐type natriuretic peptides). Impaired corin expression and function are associated with heart failure. In this study, we characterized a soluble form of corin (sCorin) and examined its effects on cardiac morphology and function in mouse heart failure models. Methods and Results sCorin, consisting of the full‐length extracellular fragment of human corin with an engineered activation site, was expressed in Chinese hamster ovary cells, purified from the conditioned medium with affinity chromatography, and characterized in pro‐ANP processing assays in vitro and pharmacokinetic studies in mice. Effects of sCorin on mouse models of heart failure induced by left coronary artery ligation and transverse aortic constriction were assessed by ELISA analysis of plasma markers, histologic examination, and echocardiography. We showed that purified and activated sCorin converted pro‐ANP to ANP that stimulated cGMP production in cultured cells. In mice, intravenously and intraperitoneally administered sCorin had plasma half‐lives of 3.5±0.1 and 8.3±0.3 hour, respectively. In the mouse heart failure models, intraperitoneal injection of sCorin increased plasma ANP, BNP, and cGMP levels; lowered plasma levels of NT‐proANP (N‐terminal‐pro‐ANP), angiotensin II, and aldosterone; reduced cardiac hypertrophy and fibrosis; and improved cardiac function. Conclusions We show that sCorin treatment enhanced natriuretic peptide processing and activity, suppressed the renin‐angiotensin‐aldosterone system, and improved cardiac morphology and function in mice with failing hearts.

Ribosomal Protein Rpl22 Regulates Development and Transformation Via Altering RNA Processing

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3878-3878 ◽  
Author(s):  
Minshi Wang ◽  
Zheng Ser ◽  
Shuyun Rao ◽  
Shawn Fahl ◽  
Yong Zhang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Processing ◽  
Rna Splicing ◽  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Read Depth ◽  
Mrna Splicing ◽  
Transformation Potential ◽  
Morpholino Oligonucleotides

Abstract Although it has long been reported that mutations in ribosome proteins (RP) are associated with increased cancer risk in humans, the molecular basis why which RP mutations do so remains unclear. Nevertheless, the prevailing view is that RP mutations, such as Rps19, are thought to alter transformation potential through general impairment of ribosome biogenesis or function. Importantly, recent observations are beginning to challenge this notion as too simplistic. We have determined that the RP, Rpl22, is not essential for ribosome biogenesis or global protein synthesis; however, its inactivation impairs the development of normal T lymphocytes and increases their transformation potential. Indeed, RPL22 is inactivated in human T acute lymphoblastic leukemia (T-ALL) and this is associated with reduced survival. Moreover, Rpl22-deficiency accelerates development of leukemia in a myristylated Akt2 transgenic (MyrAkt2 Tg) mouse model of T-ALL. To gain insight into how Rpl22 inactivation facilitates development of leukemia, we are performing unbiased transcriptomic and proteomic analysis on Rpl22+/+ and Rpl22-/- thymic lymphomas arising in the MyrAkt2 Tg model, and in an Rpl22-/- lymphoma reconstituted with Rpl22. Interestingly, relatively few changes in mRNA transcript read depth were observed; however, substantial differences in the proteome were observed. Pathway analysis revealed that the loss of Rpl22 altered the expression of proteins regulating RNA-processing, in particular RNA-splicing. Interestingly, interrogation of the transrciptome data for alternative splicing revealed that alterations in exon usage. The ability of Rpl22 to influence splicing appears to be conserved across species as alternative splicing was also observed in zebrafish embryos in which Rpl22 was knocked down using morpholino oligonucleotides. Consequently, we hypothesize that Rpl22 regulates biological events through its ability of binding to RNA targets, and controlling the expression of their protein products at least in part through altering mRNA splicing. How Rpl22 changes mRNA splicing pattern is currently under investigation. Disclosures No relevant conflicts of interest to declare.

scholarly journals CtIP -mediated alternative mRNA splicing finetunes the DNA damage response

2019 ◽  
Author(s):  
Rosario Prados-Carvajal ◽  
Guillermo Rodríguez-Real ◽  
Gabriel Gutierrez-Pozo ◽  
Pablo Huertas
Keyword(s):  
Dna Damage ◽  
Alternative Splicing ◽  
Dna Damage Response ◽  
Active Form ◽  
Mrna Splicing ◽  
Global Changes ◽  
Dna Damaging Agents ◽  
Alternative Mrna Splicing ◽  
Damage Response ◽  
In Cells

AbstractIn order to survive to the exposure of DNA damaging agents, cells activate a complex response that coordinates the cellular metabolism, cell cycle progression and DNA repair. Among many other events, recent evidence has described global changes in mRNA splicing in cells treated with genotoxic agents. Here, we explore further this DNA damage-dependent alternative splicing. Indeed, we show that both the splicing factor SF3B2 and the repair protein CtIP contribute to the global pattern of splicing both in cells treated or not to DNA damaging agents. Additionally, we focus on a specific DNA damage- and CtIP-dependent alternative splicing event of the helicase PIF1 and explore its relevance for the survival of cells upon exposure to ionizing radiation. Indeed, we described how the nuclear, active form of PIF1 is substituted by a splicing variant, named vPIF1, in a fashion that requires both the presence of DNA damage and CtIP. Interestingly, timely expression of vPIF1 is required for optimal survival to exposure to DNA damaging agents, but early expression of this isoform delays early events of the DNA damage response. On the contrary, expression of the full length PIF1 facilitates those early events, but increases the sensitivity to DNA damaging agents if the expression is maintained long-term.

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