Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers

Sivaramakrishnan, Manaswini; McCarthy, Kathleen; Campagne, Sébastien; Huber, Sylwia; Meier, Sonja; Augustin, Angélique; Heckel, Tobias; Meistermann, Hélène; Hug, Melanie N.; Birrer, Pascale; Moursy, Ahmed; Khawaja, Sarah; Schmucki, Roland; Berntenis, Nikos; Giroud, Nicolas; Golling, Sabrina; Tzouros, Manuel; Bánfai, Balázs; Durán-Pacheco, Gonzalo; Lamerz, Jens; Liu, Ying Hsiu; Luebbers, Thomas; Ratni, Hasane; Ebeling, Martin; Cléry, Antoine; Paushkin, Sergey; Krainer, Adrian R.; Allain, Frédéric H.‐T.; Metzger, Friedrich

doi:10.1038/s41467-017-01559-4

Cited by 181 publications

(212 citation statements)

References 47 publications

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“…The therapeutic strategy of small molecules targeting RNA binding unfortunately has many significant challenges. However, some critical achievements have already been reached in this field, such as the approved linezolid antibiotics, which bind RNA (38), and LMI070, which binds the pre-mRNA for survival of motor neuron 2 (SMN2) to enhance the expression of the protein in patients with spinal muscular atrophy (39,40).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling

Ding

et al. 2019

Clinical Cancer Research

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Purpose: Long noncoding RNAs (lncRNA) have essential roles in diverse cellular processes, both in normal and diseased cell types, and thus have emerged as potential therapeutic targets. A specific member of this family, the SWI/SNF complex antagonist associated with prostate cancer 1 (SChLAP1), has been shown to promote aggressive prostate cancer growth by antagonizing the SWI/SNF complex and therefore serves as a biomarker for poor prognosis. Here, we investigated whether SChLAP1 plays a potential role in the development of human glioblastoma (GBM). Experimental Design: RNA-ISH and IHC were performed on a tissue microarray to assess expression of SChLAP1 and associated proteins in human gliomas. Proteins complexed with SChLAP1 were identified using RNA pull-down and mass spectrometry. Lentiviral constructs were used for functional analysis in vitro and in vivo. Results: SChLAP1 was increased in primary GBM samples and cell lines, and knockdown of the lncRNA suppressed growth. SChLAP1 was found to bind heterogeneous nuclear ribonucleoprotein L (HNRNPL), which stabilized the lncRNA and led to an enhanced interaction with the protein actinin alpha 4 (ACTN4). ACTN4 was also highly expressed in primary GBM samples and was associated with poorer overall survival in glioma patients. The SChLAP1–HNRNPL complex led to stabilization of ACTN4 through suppression of proteasomal degradation, which resulted in increased nuclear localization of the p65 subunit of NF-κB and activation of NF-κB signaling, a pathway associated with cancer development. Conclusions: Our results implicated SChLAP1 as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling

Ding

et al. 2019

Clinical Cancer Research

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“…Accurate annotation of genes also has an enormous influence on drug discovery. Gene therapies already allow direct manipulation of the genome, transcripts can be targeted with oligonucleotides, and exon splicing events can be adjusted by small molecules …”

Section: Introductionmentioning

confidence: 99%

The Protein‐Coding Human Genome: Annotating High‐Hanging Fruits

et al. 2019

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The major transcript variants of human protein-coding genes are annotated to a certain degree of accuracy combining manual curation, transcript data, and proteomics evidence. However, there is considerable disagreement on the annotation of about 2000 genes-they can be protein-coding, noncoding, or pseudogenes-and on the annotation of most of the predicted alternative transcripts. Pure transcriptome mapping approaches seem to be limited in discriminating functional expression from noise. These limitations have partially been overcome by dedicated algorithms to detect alternative spliced micro-exons and wobble splice variants. Recently, knowledge about splice mechanism and protein structure are incorporated into an algorithm to predict neighboring homologous exons, often spliced in a mutually exclusive manner. Predicted exons are evaluated by transcript data, structural compatibility, and evolutionary conservation, revealing hundreds of novel coding exons and splice mechanism re-assignments. The emerging human pan-genome is necessitating distinctive annotations incorporating differences between individuals and between populations.

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“…Większość leków stanowią inhibitory białek enzymatycznych lub receptorów. Okazało się jednak, że możliwe jest pozyskanie wybiórczych modulatorów oddziaływań w kompleksach RNA-RNA i RNA-białko [27]. Jak na razie jednak, wiedza na temat struktury przestrzennej takich kompleksów jest zbyt mała, aby możliwe było jej wykorzystanie do racjonalnego projektowania potencjalnych leków działających poprzez taki mechanizm.…”

Section: Drobnocząsteczkowe Masunclassified

Therapeutic targeting of alternative splicing

Paluszczak¹

2019

Farm Pol.

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O dkrycie nieciągłej struktury genów przez Roberts'a i Sharp'a, uhonorowanych za to osiągnięcie Nagrodą Nobla w dziedzinie fizjologii i medycyny w roku 1993, ujawniło istnienie procesu składania (ang. splicing) pierwotnego transkryptu (pre-mRNA) w organizmach eukariotycznych, obejmującego wycinanie intronów i łączenie eksonów w dojrzały transkrypt, który jest matrycą w procesie biosyntezy białka (translacji) [1]. Obecnie wiemy, że w genomie człowieka większość genów zawiera 3-8 intronów (przeciętnie-7-8) [2]. Jednym z rekordzistów jest gen DMD, który zawiera ich aż 78. Istnieje także niewielka pula genów (~680), które nie zawierają w swojej sekwencji intronów [3]. Wyniki badań nad wycinaniem intronów nie tylko wskazały na fascynującą złożoność procesu ekspresji genów, ale znalazły też praktyczne zastosowanie w projektowaniu nowych form terapii. Ten drugi aspekt jest tematem niniejszego artykułu. Proces składania RNA W procesie transkrypcji informacja zapisana w genie zostaje przepisana z DNA na sekwencję pre-mRNA, który następnie ulega obróbce, na którą składają się trzy podstawowe procesy: dodanie czapeczki do końca 5', dodanie traktu poliadeninowego (ogona poliA) do końca 3', a także wycięcie sekwencji niekodujących (intronów) i połączenie eksonów [4]. Procesy te zachodzą przeważnie równocześnie z transkrypcją. W wyniku takiej obróbki powstaje dojrzały, pozbawiony intronów, transkrypt, który zostaje przetransportowany z jądra komórkowego do cytoplazmy, gdzie zachodzi proces biosyntezy białka. Wycięcie intronu wymaga pełnej precyzji, Therapeutic targeting of alternative splicing • Gene transcription leads to the generation of pre-mRNA molecules which contain both coding sequences (exons) and intervening non-coding sequences (introns). The primary transcript needs further processing which involves the excision of introns and ligation of exons. This process is called RNA splicing. Nearly all primary transcripts undergo alternative forms of splicing, which may lead to exon skipping or intron inclusion in the final mRNA. Thus, the translation of alternatively spliced RNA molecules results in the formation of slightly different proteins, which may, in some cases, exert antagonistic activity. Splicing is a multistage process which is conducted by a complex machinery comprising small nuclear RNA molecules and many proteins called splicing factors. The process undergoes precise regulation by means of cis acting internal RNA sequences and trans acting protein factors which may either enhance or silence the splicing of an exon. Many diseases are associated with aberrations of alternative splicing and its modulation may be used therapeutically, e.g. for the treatment of spinal muscular atrophy (SMA) or Duchenne muscular dystrophy (DMD). This article presents current knowledge of the ways of pharmacological modulation of alternative splicing. The focus is on the use of those therapeutics which have been already approved for clinical application or have entered clinical trials. The chemistry and mechanism of action of specif...

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Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers

Cited by 181 publications

References 47 publications

Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling

Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling

The Protein‐Coding Human Genome: Annotating High‐Hanging Fruits

Therapeutic targeting of alternative splicing

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