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Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Sarah L Stenton, Susan Walker, Alicia Ljungdahl, Jenny Lord, Vijay S Ganesh, Jialan Ma, Alexandra C Martin-Geary, Gabrielle Lemire, Elston N D'Souza, Shan Dong, Jamie M Ellingford, David R Adams, Kirsten Allan, Madhura Bakshi, Erin E Baldwin, Seth I Berger, Jonathan A Bernstein, Natasha J Brown, Lindsay C Burrage, Kimberly Chapman, Alison G Compton, Chloe A Cunningham, Precilla D'Souza, Emmanuèle C Délot, Kerith-Rae Dias, Ellen R Elias, Carey-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L Fraser, Lyndon Gallacher, Casie A Genetti, Christina L Grant, Tobias Haack, Alma Kuechler, Seema R Lalani, Elsa Leitão, Anna Le Fevre, Richard J Leventer, Jan E Liebelt, Paul J Lockhart, Alan S Ma, Ellen F Macnamara, Taylor M Maurer, Hector R Mendez, Stephen B Montgomery, Marie-Cécile Nassogne, Serena Neumann, Melanie O'Leary, Elizabeth E Palmer, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L Rehm, Chloe M Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A Rosenfeld, Rani Sachdev, Cas Simons, Sanjay M Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Tiong Yang Tan, Natalie B Tan, Suzanna El Temple, David R Thorburn, Cynthia J Tifft, Eloise Uebergang, Grace E VanNoy, Eric Vilain, David H Viskochil, Laura Wedd, Matthew T Wheeler, Susan M White, Monica Wojcik, Lynne A Wolfe, Zoe Wolfenson, Changrui Xiao, David Zocche, John L Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M Fica, Diana Baralle, Christel Depienne, Daniel G MacArthur, Joanna Mm Howson, Stephan J Sanders, Anne O'Donnell-Luria, Nicola Whiffin
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD...
April 9, 2024: medRxiv
#2
JOURNAL ARTICLE
Matheus H Dias, Vladyslava Liudkovska, Jasmine Montenegro Navarro, Lisanne Giebel, Julien Champagne, Chrysa Papagianni, Onno B Bleijerveld, Arno Velds, Reuven Agami, René Bernards, Maciej Cieśla
Perturbation of protein phosphorylation represents an attractive approach to cancer treatment. Besides kinase inhibitors, protein phosphatase inhibitors have been shown to have anti-cancer activity. A prime example is the small molecule LB-100, an inhibitor of protein phosphatases 2A/5 (PP2A/PP5), enzymes that affect cellular physiology. LB-100 has proven effective in pre-clinical models in combination with immunotherapy, but the molecular underpinnings of this synergy remain understood poorly. We report here a sensitivity of the mRNA splicing machinery to phosphorylation changes in response to LB-100 in colorectal adenocarcinoma...
April 10, 2024: EMBO Reports
#3
REVIEW
Uri Mbonye, Jonathan Karn
Transcriptionally latent forms of replication-competent proviruses, present primarily in a small subset of memory CD4+ T cells, pose the primary barrier to a cure for HIV-1 infection because they are the source of the viral rebound that almost inevitably follows the interruption of antiretroviral therapy. Over the last 30 years, many of the factors essential for initiating HIV-1 transcription have been identified in studies performed using transformed cell lines, such as the Jurkat T-cell model. However, as highlighted in this review, several poorly understood mechanisms still need to be elucidated, including the molecular basis for promoter-proximal pausing of the transcribing complex and the detailed mechanism of the delivery of P-TEFb from 7SK snRNP...
April 5, 2024: Retrovirology
#4
JOURNAL ARTICLE
Andrey Damianov, Chia-Ho Lin, Jeffrey Huang, Lin Zhou, Yasaman Jami-Alahmadi, Parham Peyda, James Wohlschlegel, Douglas L Black
Understanding the mechanisms of pre-mRNA splicing is limited by the technical challenges to examining spliceosomes in vivo. Here, we report the isolation of RNP complexes derived from precatalytic A or B-like spliceosomes solubilized from the chromatin pellet of mammalian cell nuclei. We found that these complexes contain U2 snRNP proteins and a portion of the U2 snRNA bound with protected RNA fragments that precisely map to intronic branch sites across the transcriptome. These U2 complexes also contained the splicing regulators RBM5 and RBM10...
March 21, 2024: Molecular Cell
#5
JOURNAL ARTICLE
Dong Jiang, Xia-Ling Zhu, Yan An, Yi-Ran Li
BACKGROUND & AIMS: Small nuclear ribonucleoprotein U1 subunit 70 (SNRNP70) as one of the components of the U1 small nuclear ribonucleoprotein (snRNP) is rarely reported in cancers. This study aims to estimate the application potential of SNRNP70 in hepatocellular carcinoma (HCC) clinical practice. METHODS: Based on the TCGA database and cohort of HCC patients, we investigated the expression patterns and prognostic value of SNRNP70 in HCC. Then, the combination of SNRNP70 and alpha-fetoprotein (AFP) in 278 HCC cases was analyzed...
2024: PeerJ
#6
JOURNAL ARTICLE
Antto J Norppa, Iftekhar Chowdhury, Laura E van Rooijen, Janne J Ravantti, Berend Snel, Markku Varjosalo, Mikko J Frilander
Here, we identify RBM41 as a novel unique protein component of the minor spliceosome. RBM41 has no previously recognized cellular function but has been identified as a paralog of U11/U12-65K, a known unique component of the U11/U12 di-snRNP. Both proteins use their highly similar C-terminal RRMs to bind to 3'-terminal stem-loops in U12 and U6atac snRNAs with comparable affinity. Our BioID data indicate that the unique N-terminal domain of RBM41 is necessary for its association with complexes containing DHX8, an RNA helicase, which in the major spliceosome drives the release of mature mRNA from the spliceosome...
March 18, 2024: Nucleic Acids Research
#7
JOURNAL ARTICLE
Rui Bai, Meng Yuan, Pu Zhang, Ting Luo, Yigong Shi, Ruixue Wan
The minor spliceosome, which is responsible for the splicing of U12-type introns, comprises five small nuclear RNAs (snRNAs), of which only one is shared with the major spliceosome. In this work, we report the 3.3-angstrom cryo-electron microscopy structure of the fully assembled human minor spliceosome pre-B complex. The atomic model includes U11 small nuclear ribonucleoprotein (snRNP), U12 snRNP, and U4atac/U6atac.U5 tri-snRNP. U11 snRNA is recognized by five U11-specific proteins (20K, 25K, 35K, 48K, and 59K) and the heptameric Sm ring...
March 15, 2024: Science
#8
JOURNAL ARTICLE
Sarah Schneider, Irina Brandina, Daniel Peter, Sonal Lagad, Angelique Fraudeau, Júlia Portell-Montserrat, Jonas Tholen, Jiangfeng Zhao, Wojciech P Galej
The 20S U5 small nuclear ribonucleoprotein particle (snRNP) is a 17-subunit RNA-protein complex and a precursor of the U4/U6.U5 tri-snRNP, the major building block of the precatalytic spliceosome. CD2BP2 is a hallmark protein of the 20S U5 snRNP, absent from the mature tri-snRNP. Here we report a high-resolution cryogenic electron microscopy structure of the 20S U5 snRNP, shedding light on the mutually exclusive interfaces utilized during tri-snRNP assembly and the role of the CD2BP2 in facilitating this process...
March 11, 2024: Nature Structural & Molecular Biology
#9
JOURNAL ARTICLE
Daria Riabov Bassat, Supapat Visanpattanasin, Matthias K Vorländer, Laura Fin, Alexander W Phillips, Clemens Plaschka
Pre-mRNA splicing by the spliceosome requires the biogenesis and recycling of its small nuclear ribonucleoprotein (snRNP) complexes, which are consumed in each round of splicing. The human U5 snRNP is the ~1 MDa 'heart' of the spliceosome and is recycled through an unknown mechanism involving major architectural rearrangements and the dedicated chaperones CD2BP2 and TSSC4. Late steps in U5 snRNP biogenesis similarly involve these chaperones. Here we report cryo-electron microscopy structures of four human U5 snRNP-CD2BP2-TSSC4 complexes, revealing how a series of molecular events primes the U5 snRNP to generate the ~2 MDa U4/U6...
March 11, 2024: Nature Structural & Molecular Biology
#10
JOURNAL ARTICLE
Sebastien Campagne
The U1 small ribonucleoprotein (U1 snRNP) plays a pivotal role in the intricate process of gene expression, specifically within nuclear RNA processing. By initiating the splicing reaction and modulating 3'-end processing, U1 snRNP exerts precise control over RNA metabolism and gene expression. This ribonucleoparticle is abundantly present, and its complex biogenesis necessitates shuttling between the nuclear and cytoplasmic compartments. Over the past three decades, extensive research has illuminated the crucial connection between disrupted U snRNP biogenesis and several prominent human diseases, notably various neurodegenerative conditions...
March 9, 2024: Chembiochem: a European Journal of Chemical Biology
#11
JOURNAL ARTICLE
Kenna Sarka, Sol Katzman, Alan M Zahler
In spliceosome assembly, the 5' splice site is initially recognized by U1snRNA. U1 leaves the spliceosome during the assembly process, therefore other factors contribute to maintenance of 5' splice site identity as it is loaded into the catalytic site. Recent structural data suggest that human tri-snRNP 27K (SNRP27) M141 and SNU66 H734 interact to stabilize the U4/U6 quasi-pseudo knot at the base of the U6 snRNA ACAGAGA box in pre-B complex. Previously, we found that mutations in C. elegans at SNRP-27 M141 promote changes in alternative 5'ss usage...
March 5, 2024: RNA
#12
JOURNAL ARTICLE
Minshu Zou, Qiuju Song, Taiyong Yin, Hongtao Xu, Guoming Nie
OBJECTIVE: In this study, we investigated the development of the Wnt signaling pathway in vitamin D (VitD) to improve systemic lupus erythematosus in mice to breakthrough clinical treatment approaches. METHODS: Body weight changes were recorded during rearing. Antinuclear antibodies (ANA), anti-dsDNA, and anti-snRNP were detected in the mouse serum using an enzyme-linked immunosorbent assay. Apoptosis of Th1 and Th2 immune cells in mice was detected using flow cytometry...
February 2024: Immunity, Inflammation and Disease
#13
JOURNAL ARTICLE
Gaurav Sharma, Martina Paganin, Fabio Lauria, Elena Perenthaler, Gabriella Viero
The underlying cause of Spinal Muscular Atrophy (SMA) is in the reduction of survival motor neuron (SMN) protein levels due to mutations in the SMN1 gene. The specific effects of SMN protein loss and the resulting pathological alterations are not fully understood. Given the crucial roles of the SMN protein in snRNP biogenesis and its interactions with ribosomes and translation-related proteins and mRNAs, a decrease in SMN levels below a specific threshold in SMA is expected to affect translational control of gene expression...
February 23, 2024: Biochemical Society Transactions
#14
JOURNAL ARTICLE
Pablo Iruzubieta, Alberto Damborenea, Mihaela Ioghen, Simon Bajew, Roberto Fernandez-Torrón, Ana Töpf, Álvaro Herrero-Reiriz, Diana Epure, Katharina Vill, Aurelio Hernández-Laín, María Manterola, Mikel Azkargorta, Oihane Pikatza-Menoio, Laura Pérez-Fernandez, Mikel García-Puga, Gisela Gaina, Alexandra Bastian, Ioana Streata, Maggie C Walter, Wolfgang Müller-Felber, Simone Thiele, Saioa Moragón, Nerea Bastida-Lertxundi, Aitziber López-Cortajarena, Felix Elortza, Gorka Gereñu, Sonia Alonso-Martin, Volker Straub, David de Sancho, Raluca Teleanu, Adolfo López de Munain, Lorea Blázquez
Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome...
February 15, 2024: Brain
#15
Tucker J Carrocci, Samuel DeMario, Kevin He, Natalie J Zeps, Cade T Harkner, Guillaume Chanfreau, Aaron A Hoskins
Identification of splice sites is a critical step in pre-mRNA splicing since definition of the exon/intron boundaries controls what nucleotides are incorporated into mature mRNAs. The intron boundary with the upstream exon is initially identified through interactions with the U1 snRNP. This involves both base pairing between the U1 snRNA and the pre-mRNA as well as snRNP proteins interacting with the 5' splice site/snRNA duplex. In yeast, this duplex is buttressed by two conserved protein factors, Yhc1 and Luc7...
February 4, 2024: bioRxiv
#16
JOURNAL ARTICLE
Dimitrije Stanković, Luke S Tain, Mirka Uhlirova
Co-transcriptional processing of nascent pre-mRNAs by the spliceosome is vital to regulating gene expression and maintaining genome integrity. Here, we show that the deficiency of functional U5 small nuclear ribonucleoprotein particles (snRNPs) in Drosophila imaginal cells causes extensive transcriptome remodeling and accumulation of highly mutagenic R-loops, triggering a robust stress response and cell cycle arrest. Despite compromised proliferative capacity, the U5 snRNP-deficient cells increased protein translation and cell size, causing intra-organ growth disbalance before being gradually eliminated via apoptosis...
February 2, 2024: Nucleic Acids Research
#17
JOURNAL ARTICLE
Salla Kyheröinen, Bina Prajapati, Maria Sokolova, Maximilian Schmitz, Tiina Viita, Matthias Geyer, Maria K Vartiainen
Nuclear actin has been demonstrated to be essential for optimal transcription, but the molecular mechanisms and direct binding partner for actin in the RNA polymerase complex have remained unknown. By using purified proteins in a variety of biochemical assays, we demonstrate a direct and specific interaction between monomeric actin and Cdk9, the kinase subunit of the positive transcription elongation factor b (P-TEFb) required for RNA polymerase II pause-release. This interaction efficiently prevents actin polymerization, is not dependent on kinase activity of Cdk9 and is not involved with releasing P-TEFb from its inhibitor 7SK snRNP complex...
January 30, 2024: Journal of Biological Chemistry
#18
JOURNAL ARTICLE
Xiaofeng Zhang, Xiechao Zhan, Tong Bian, Fenghua Yang, Pan Li, Yichen Lu, Zhihan Xing, Rongyan Fan, Qiangfeng Cliff Zhang, Yigong Shi
Selection of the pre-mRNA branch site (BS) by the U2 small nuclear ribonucleoprotein (snRNP) is crucial to prespliceosome (A complex) assembly. The RNA helicase PRP5 proofreads BS selection but the underlying mechanism remains unclear. Here we report the atomic structures of two sequential complexes leading to prespliceosome assembly: human 17S U2 snRNP and a cross-exon pre-A complex. PRP5 is anchored on 17S U2 snRNP mainly through occupation of the RNA path of SF3B1 by an acidic loop of PRP5; the helicase domain of PRP5 associates with U2 snRNA; the BS-interacting stem-loop (BSL) of U2 snRNA is shielded by TAT-SF1, unable to engage the BS...
January 9, 2024: Nature Structural & Molecular Biology
#19
JOURNAL ARTICLE
Honggen Yuan, Jia Hui Zou, Yun Luo, Jinhua Zhang, Hong Pan, Shengbo Cao, Huanchun Chen, Yunfeng Song
Japanese encephalitis virus (JEV) is a zoonotic pathogen belonging to the Flavivirus genus, causing viral encephalitis in humans and reproductive failure in swine. The 3' untranslated region (3'UTR) of JEV contains highly conservative secondary structures required for viral translation, RNA synthesis, and pathogenicity. Identification of host factors interacting with JEV 3'UTR is crucial for elucidating the underlying mechanism of flavivirus replication and pathogenesis. In this study, U2 snRNP auxiliary factor 2 (U2AF2) was identified as a novel cellular protein that interacts with the JEV genomic 3'UTR (the SL-I, SL-II, SL-III, and DB region) via its 1 to 148 amino acids...
January 3, 2024: Veterinary Microbiology
#20
Subbaiah Chalivendra, Shasha Shi, Xueni Li, Zhiling Kuang, Joseph Giovinazzo, Lingdi Zhang, John Rossi, Anthony J Saviola, Jingxin Wang, Robb Welty, Shiheng Liu, Katherine Vaeth, Z Hong Zhou, Kirk C Hansen, J Matthew Taliaferro, Rui Zhao
The recognition of 5' splice site (5' ss) is one of the earliest steps of pre-mRNA splicing. To better understand the mechanism and regulation of 5' ss recognition, we selectively humanized components of the yeast U1 snRNP to reveal the function of these components in 5' ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yeast U1 (yU1) snRNA and the 5' ss RNA duplex. We replaced the Zinc-Finger (ZnF) domain of yU1C with its human counterpart, which resulted in cold-sensitive growth phenotype and moderate splicing defects...
December 15, 2023: bioRxiv
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