The Experts below are selected from a list of 1866 Experts worldwide ranked by ideXlab platform
Michelle Newman - One of the best experts on this subject based on the ideXlab platform.
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the g quadruplex specific rna helicase DHX36 regulates p53 pre mrna 3 end processing following uv induced dna damage
Journal of Molecular Biology, 2017Co-Authors: Rym Sfaxi, Michelle Newman, Abhijit Saha, David Monchaud, Mariepaule Teuladefichou, Stephan VagnerAbstract:Pre-mRNA 3′-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3′-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3′-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3′-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands (PNADOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3′-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV.
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the g quadruplex specific rna helicase DHX36 regulates p53 pre mrna 3 end processing following uv induced dna damage
Journal of Molecular Biology, 2017Co-Authors: Michelle Newman, Rym Sfaxi, Abhijit Saha, David Monchaud, Mariepaule Teuladefichou, Stephan VagnerAbstract:Pre-mRNA 3 '-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3 '-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3 '-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3 '-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands ((PNA)DOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3 '-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV. (C) 2016 Elsevier Ltd. All rights reserved.
Stephan Vagner - One of the best experts on this subject based on the ideXlab platform.
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the g quadruplex specific rna helicase DHX36 regulates p53 pre mrna 3 end processing following uv induced dna damage
Journal of Molecular Biology, 2017Co-Authors: Rym Sfaxi, Michelle Newman, Abhijit Saha, David Monchaud, Mariepaule Teuladefichou, Stephan VagnerAbstract:Pre-mRNA 3′-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3′-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3′-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3′-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands (PNADOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3′-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV.
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the g quadruplex specific rna helicase DHX36 regulates p53 pre mrna 3 end processing following uv induced dna damage
Journal of Molecular Biology, 2017Co-Authors: Michelle Newman, Rym Sfaxi, Abhijit Saha, David Monchaud, Mariepaule Teuladefichou, Stephan VagnerAbstract:Pre-mRNA 3 '-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3 '-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3 '-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3 '-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands ((PNA)DOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3 '-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV. (C) 2016 Elsevier Ltd. All rights reserved.
Raissa Kay - One of the best experts on this subject based on the ideXlab platform.
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pathogenic variants in the deah box rna helicase dhx37 are a frequent cause of 46 xy gonadal dysgenesis and 46 xy testicular regression syndrome
Genetics in Medicine, 2020Co-Authors: Ken Mcelreavey, Joelle Bignontopalovic, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Raissa KayAbstract:XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10−10). Five variants are de novo (P value = 1.5 × 10−5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
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Pathogenic variants in the DEAH-box RNA helicase DHX37 are a frequent cause of 46,XY gonadal dysgenesis and 46,XY testicular regression syndrome
Genetics in Medicine, 2019Co-Authors: Ken Mcelreavey, Anne Jorgensen, Caroline Eozenou, Tiphanie Merel, Daisylyn Senna Tan, Denis Houzelstein, Federica Buonocore, Nick Warr, Joelle Bignon-topalovic, Raissa KayAbstract:PURPOSE: XY individuals with disorders/differences of sex development (DSD) are characterized by reduced androgenization caused, in some children, by gonadal dysgenesis or testis regression during fetal development. The genetic etiology for most patients with 46,XY gonadal dysgenesis and for all patients with testicular regression syndrome (TRS) is unknown. METHODS: We performed exome and/or Sanger sequencing in 145 individuals with 46,XY DSD of unknown etiology including gonadal dysgenesis and TRS. RESULTS: Thirteen children carried heterozygous missense pathogenic variants involving the RNA helicase DHX37, which is essential for ribosome biogenesis. Enrichment of rare/novel DHX37 missense variants in 46,XY DSD is highly significant compared with controls (P value = 5.8 × 10-10). Five variants are de novo (P value = 1.5 × 10-5). Twelve variants are clustered in two highly conserved functional domains and were specifically associated with gonadal dysgenesis and TRS. Consistent with a role in early testis development, DHX37 is expressed specifically in somatic cells of the developing human and mouse testis. CONCLUSION: DHX37 pathogenic variants are a new cause of an autosomal dominant form of 46,XY DSD, including gonadal dysgenesis and TRS, showing that these conditions are part of a clinical spectrum. This raises the possibility that some forms of DSD may be a ribosomopathy.
Rym Sfaxi - One of the best experts on this subject based on the ideXlab platform.
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the g quadruplex specific rna helicase DHX36 regulates p53 pre mrna 3 end processing following uv induced dna damage
Journal of Molecular Biology, 2017Co-Authors: Michelle Newman, Rym Sfaxi, Abhijit Saha, David Monchaud, Mariepaule Teuladefichou, Stephan VagnerAbstract:Pre-mRNA 3 '-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3 '-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3 '-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3 '-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands ((PNA)DOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3 '-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV. (C) 2016 Elsevier Ltd. All rights reserved.
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the g quadruplex specific rna helicase DHX36 regulates p53 pre mrna 3 end processing following uv induced dna damage
Journal of Molecular Biology, 2017Co-Authors: Rym Sfaxi, Michelle Newman, Abhijit Saha, David Monchaud, Mariepaule Teuladefichou, Stephan VagnerAbstract:Pre-mRNA 3′-end processing, the process through which almost all eukaryotic mRNAs acquire a poly(A) tail is generally inhibited during the cellular DNA damage response leading to a profound impact on the level of protein expression since unprocessed transcripts at the 3′-end will be degraded or unable to be transported to the cytoplasm. However, a compensatory mechanism involving the binding of the hnRNP H/F family of RNA binding proteins to an RNA G-quadruplex (G4) structure located in the vicinity of a polyadenylation site has previously been described to allow the transcript encoding the p53 tumour suppressor protein to be properly processed during DNA damage and to provide the cells with a way to react to DNA damage. Here we report that the DEAH (Asp-Glu-Ala-His) box RNA helicase DHX36/RHAU/G4R1, which specifically binds to and resolves parallel-stranded G4, is necessary to maintain p53 pre-mRNA 3′-end processing following UV-induced DNA damage. DHX36 binds to the p53 RNA G4, while mutation of the G4 impairs the ability of DHX36 to maintain pre-mRNA 3′-end processing. Stabilization of the p53 RNA G4 with two different G4 ligands (PNADOTASQ and PhenDC3), which is expected from previous studies to prevent DHX36 from binding and unwinding G4s, also impairs p53 pre-mRNA 3′-end processing following UV. Our work identifies DHX36 as a new actor in the compensatory mechanisms that are in place to ensure that the mRNAs encoding p53 are still processed following UV.
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regulation de la maturation en 3 des pre arnm en reponse aux dommages de l adn
2017Co-Authors: Rym SfaxiAbstract:La maturation 3’ des pre-ARNm constitue une etape majeure dans la regulation post-transcriptionnelle de l’expression des genes, indispensable a la stabilite, l’export vers le cytoplasme et la traduction des ARNm. Elle est composee de deux reactions : un clivage a l’extremite 3’ suivie de l’addition d’une queue poly(A). Des etudes ont montre que la maturation en 3’ est inhibee en reponse aux dommages de l’ADN. Cependant, la cellule a mis en place des mecanismes compensatoires qui permettent a certains pre-ARNm d’etre correctement matures assurant ainsi le maintien de son integrite. Les travaux que nous avons menes ont mis en evidence un mecanisme de resistance a l’inhibition de maturation en 3’ du pre-ARNm codant pour le suppresseur de tumeur p53. Ce mecanisme fait intervenir l’helicase DHX36 qui deplie une structure secondaire appelee G-quadruplexe situee en aval du site de clivage. Par ailleurs dans une deuxieme etude, nous avons montre que la maturation en 3’ maintenue du pre-ARNm p53 en reponse aux dommages de l’ADN, est decouplee du processus de transcription, contrairement au pre-ARNm TBP dont la maturation 3’ est inhibee en reponse aux dommage de l’ADN. Ce decouplage a lieu grâce a un clivage co-transcriptionnelle du pre-ARNm p53 au niveau de la chromatine qui entraine sa liberation dans le nucleoplasme ou il subit sa maturation en 3’. Une etude a grande echelle nous a permis de montrer que ce mecanisme de maturation en 3’ survenant dans le nucleoplasme est associe au maintien d'une maturation en 3’ efficace en reponse aux dommages de l’ADN.
Shankar Balasubramanian - One of the best experts on this subject based on the ideXlab platform.
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correction to rna g quadruplexes at upstream open reading frames cause DHX36 and dhx9 dependent translation of human mrnas
Genome Biology, 2019Co-Authors: Pierre Murat, Giovanni Marsico, Barbara Herdy, Avazeh Ghanbarian, Guillem Portella, Shankar BalasubramanianAbstract:Following publication of the original article [1], the authors reported the following error in the name of the fourth author.
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rna g quadruplexes at upstream open reading frames cause DHX36 and dhx9 dependent translation of human mrnas
Genome Biology, 2018Co-Authors: Pierre Murat, Giovanni Marsico, Barbara Herdy, Avazeh Ghanbarian, Guillem Portella, Shankar BalasubramanianAbstract:RNA secondary structures in the 5′-untranslated regions (5′-UTR) of mRNAs are key to the post-transcriptional regulation of gene expression. While it is evident that non-canonical Hoogsteen-paired G-quadruplex (rG4) structures somehow contribute to the regulation of translation initiation, the nature and extent of human mRNAs that are regulated by rG4s is not known. Here, we provide new insights into a mechanism by which rG4 formation modulates translation. Using transcriptome-wide ribosome profiling, we identify rG4-driven mRNAs in HeLa cells and reveal that rG4s in the 5′-UTRs of inefficiently translated mRNAs associate with high ribosome density and the translation of repressive upstream open reading frames (uORF). We demonstrate that depletion of the rG4-unwinding helicases DHX36 and DHX9 promotes translation of rG4-associated uORFs while reducing the translation of coding regions for transcripts that comprise proto-oncogenes, transcription factors and epigenetic regulators. Transcriptome-wide identification of DHX9 binding sites shows that reduced translation is mediated through direct physical interaction between the helicase and its rG4 substrate. This study identifies human mRNAs whose translation efficiency is modulated by the DHX36- and DHX9-dependent folding/unfolding of rG4s within their 5′-UTRs. We reveal a previously unknown mechanism for translation regulation in which unresolved rG4s within 5′-UTRs promote 80S ribosome formation on upstream start codons, causing inhibition of translation of the downstream main open reading frames. Our findings suggest that the interaction of helicases with rG4s could be targeted for future therapeutic intervention.
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structural basis of g quadruplex unfolding by the deah rha helicase DHX36
Nature, 2018Co-Authors: Michael C. Chen, Ramreddy Tippana, Sua Myong, Pierre Murat, Shankar Balasubramanian, N Demeshkina, Adrian R FerredamareAbstract:Guanine-rich nucleic acid sequences challenge the replication, transcription, and translation machinery by spontaneously folding into G-quadruplexes, the unfolding of which requires forces greater than most polymerases can exert1,2. Eukaryotic cells contain numerous helicases that can unfold G-quadruplexes 3 . The molecular basis of the recognition and unfolding of G-quadruplexes by helicases remains poorly understood. DHX36 (also known as RHAU and G4R1), a member of the DEAH/RHA family of helicases, binds both DNA and RNA G-quadruplexes with extremely high affinity4–6, is consistently found bound to G-quadruplexes in cells7,8, and is a major source of G-quadruplex unfolding activity in HeLa cell lysates 6 . DHX36 is a multi-functional helicase that has been implicated in G-quadruplex-mediated transcriptional and post-transcriptional regulation, and is essential for heart development, haematopoiesis, and embryogenesis in mice9–12. Here we report the co-crystal structure of bovine DHX36 bound to a DNA with a G-quadruplex and a 3′ single-stranded DNA segment. We show that the N-terminal DHX36-specific motif folds into a DNA-binding-induced α-helix that, together with the OB-fold-like subdomain, selectively binds parallel G-quadruplexes. Comparison with unliganded and ATP-analogue-bound DHX36 structures, together with single-molecule fluorescence resonance energy transfer (FRET) analysis, suggests that G-quadruplex binding alone induces rearrangements of the helicase core; by pulling on the single-stranded DNA tail, these rearrangements drive G-quadruplex unfolding one residue at a time. A mechanism for the unfolding of guanine-rich DNA ‘quadruplexes’ by helicases is suggested, based on the structure of a DNA-bound helicase.
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Additional file 1: of RNA G-quadruplexes at upstream open reading frames cause DHX36- and DHX9-dependent translation of human mRNAs
2018Co-Authors: Pierre Murat, Giovanni Marsico, Barbara Herdy, Avazeh Ghanbarian, Guillem Portella, Shankar BalasubramanianAbstract:Figure S1. Ribosome profiling of HeLa cells. Figure S2. Biophysical characterization of the rG4 motif found in the 5′-UTR of EED. Figure S3. Characterization of 5′-UTR translation in HeLa cells. Figure S4. Contribution of known cis-regulatory elements to translation efficiency. Figure S5. Principal component analysis (PCA) and statistical modelling of RPFdist variation. Figure S6. Polysome profiling allows assessing helicase enrichment in polysomes. Figure S7. Ribosome profiling defines the role of DHX36 and DHX9 in translation. Figure S8. Motifs discovery and analysis within the 5′-UTR of DHX9- and DHX36-dependent mRNAs. Figure S9. Characterization of DHX36- and DHX9-dependent uORFs. Figure S10. Reproducibility of the DHX9 iCLIP experiment. Figure S11. Characterization of DHX9 iCLIP peaks. Figure S12. Biophysical characterization of the rG4 motif found in the 5′-UTR of DDX23. Figure S13. DHX36- and DHX9-dependent transcripts. Figure S14. Mutation and expression profiles of DHX36 and DHX9 in cancer. Figure S15. rG4s stimulate the repressive effect of uORFs in a DHX36- and DHX9- dependent manner. (PDF 5852 kb
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Additional file 5: of RNA G-quadruplexes at upstream open reading frames cause DHX36- and DHX9-dependent translation of human mRNAs
2018Co-Authors: Pierre Murat, Giovanni Marsico, Barbara Herdy, Avazeh Ghanbarian, Guillem Portella, Shankar BalasubramanianAbstract:ORFscores for all putative uORF in non-treated, control, DHX36- and DHX9-depleted HeLa cells. (XLS 12540 kb