Genes & Development, Год журнала: 2023, Номер 37(21-24), С. 945 - 947
Опубликована: Ноя. 1, 2023
RNA helicases orchestrate proofreading mechanisms that facilitate accurate intron removal from pre-mRNAs. How these activities are recruited to spliceosome/pre-mRNA complexes remains poorly understood. In this issue of
Язык: Английский
Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(9), С. 683 - 700
Опубликована: Май 21, 2024
Язык: Английский
Процитировано
16
Molecular Cell, Год журнала: 2024, Номер 84(19), С. 3667 - 3680
Опубликована: Авг. 14, 2024
Somatic mutations in genes encoding components of the RNA splicing machinery occur frequently multiple forms cancer. The most mutated factors cancer impact intronic branch site and 3' splice recognition. These include core factor SF3B1 as well U2AF1/2 heterodimeric complex, which recruits SF3b complex to site. Additionally, regulatory proteins SRSF2 RBM10 are frequent cancer, there has been a recent suggestion that variant small nuclear RNAs (snRNAs) may contribute dysregulation Here, we describe molecular mechanisms by these alter recognition how studies this process have yielded new insights into pathogenesis regulation splicing. We also discuss data linking mutant metabolism beyond
Язык: Английский
Процитировано
14
Cell Research, Год журнала: 2025, Номер unknown
Опубликована: Фев. 28, 2025
Abstract The spliceosome, a highly dynamic macromolecular assembly, catalyzes the precise removal of introns from pre-mRNAs. Recent studies have provided comprehensive structural insights into step-wise catalytic splicing and final disassembly spliceosome. However, molecular details how spliceosome recognizes rejects suboptimal substrates remained unclear. Here, we show cryo-electron microscopy structures spliceosomal quality control complexes thermophilic eukaryote, Chaetomium thermophilum . spliceosomes, henceforth termed B* Q , are stalled at catalytically activated state but prior to first reaction due an aberrant 5’ splice site conformation. This is recognized by G-patch protein GPATCH1, which docked onto PRP8-EN -RH domains has recruited cognate DHX35 helicase its U2 snRNA substrate. In dissociated U2/branch helix, while DHX15 close U6 RNA 3’-end Our work thus provides mechanistic concerted action two helicases in maintaining fidelity priming spliceosomes that bound for disassembly.
Язык: Английский
Процитировано
1
Current Opinion in Structural Biology, Год журнала: 2024, Номер 88, С. 102907 - 102907
Опубликована: Авг. 20, 2024
Splicing is a critical processing step during pre-mRNA maturation in eukaryotes. The correct selection of splice sites the early steps spliceosome assembly highly important and crucial for regulation alternative splicing. Splice site recognition splicing depend on cis-regulatory sequence elements RNA trans-acting factors that recognize these crosstalk with canonical machinery. Structural mechanisms involving complexes are governed by dynamic structures, protein-RNA interactions conformational flexibility multidomain binding proteins. Here, we highlight structural studies integrative biology approaches, which provide complementary information from cryo-EM, NMR, small angle scattering, X-ray crystallography to elucidate quality control, highlighting role dynamics.
Язык: Английский
Процитировано
7
Trends in Biochemical Sciences, Год журнала: 2024, Номер 49(7), С. 583 - 595
Опубликована: Апрель 18, 2024
Язык: Английский
Процитировано
6
The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(5)
Опубликована: Фев. 24, 2025
In this issue of JEM, Krishnamoorthy et al. (https://doi.org/10.1084/jem.20241029) identify the loss splicing factor RBM10 as a driver metastasis in thyroid cancer through regulation RNA splicing. The synthetic lethal interaction between NF-κB and reveals potential therapeutic vulnerability.
Язык: Английский
Процитировано
0
Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(13)
Опубликована: Март 26, 2025
Myelodysplastic syndromes and other cancers are often associated with mutations in the U2 snRNP protein SF3B1. Common SF3B1 mutations, including K700E, disrupt interaction SUGP1 induce aberrant activation of alternative 3′ splice sites (ss), presumably resulting from U2/branch site (BS) recognition by mutant spliceosome. Here, we apply a method IP-seq to profile BS binding across transcriptome K562 leukemia cells carrying K700E mutation. For ss activated identify their BSs show that they indeed shifted WT sites. Unexpectedly, also thousands additional changes do not alter splicing. These new usually very close natural sites, occur upstream or downstream, either exhibit stronger base-pairing potential snRNA adjacent polypyrimidine tracts than The widespread imprecision induced limited selection expands physiological consequences this oncogenic
Язык: Английский
Процитировано
0
Communications Biology, Год журнала: 2023, Номер 6(1)
Опубликована: Ноя. 10, 2023
The branchpoint (BP) motif is an essential intronic element for spliceosomal pre-mRNA splicing. In mammals, its sequence composition, distance to the downstream exon, and number of BPs per 3´ splice site are highly variable, unlike GT/AG dinucleotides at intron ends. These variations appear provide evolutionary advantages fostering alternative splicing, satisfying more diverse cellular contexts, promoting resilience genetic changes, thus contributing extra layer complexity gene regulation. Importantly, variants in BP itself or genes encoding BP-interacting factors cause human diseases cancers, highlighting critical function need precisely identify functional faithful interpretation their roles this perspective, we will succinctly summarize major findings related variations, discuss relevant issues/challenges, our insights.
Язык: Английский
Процитировано
6
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июль 16, 2024
Abstract The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In nucleus, most of is bound LASR, a complex RNA-binding that recognize additional motifs. However, it remains unclear how different subunits Rbfox/LASR act together bind and splicing. We used nuclease-protection assay map transcriptome-wide footprints Rbfox1/LASR on nascent cellular RNA. addition GCAUG, binds containing motifs for LASR hnRNPs M, H/F, C, Matrin3. These elements are often arranged in tandem, forming multi-part modules To distinguish contact sites Rbfox1 from subunits, we analyzed mutant Rbfox1(F125A) has lost but associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact GCAUG retain Splicing analyses reveal activating exons through adjacent elements, can also stimulate near subunits. Mini-gene experiments demonstrate these diverse produce combined regulatory effect target exon. findings illuminate decode combinatorial signals recognizing groups tandem elements.
Язык: Английский
Процитировано
1
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Июль 30, 2024
The splicing factor RNA-binding motif protein 10 (RBM10) is frequently mutated in lung adenocarcinoma (LUAD) (9-25%). Most RBM10 cancer mutations are loss-of-function, correlating with increased tumorigenesis and limiting the efficacy of current LUAD targeted therapies. Remarkably, therapeutic strategies leveraging deficiency remain unexplored. Here, we conduct a CRISPR-Cas9 synthetic lethality (SL) screen identify ~60 SL genes, including WEE1 kinase. inhibition sensitizes RBM10-deficient cells in-vitro in-vivo. Mechanistically, splicing-independent role regulating DNA replication fork progression stress response, which underpins RBM10-WEE1 SL. Additionally, interacts active forks, relying on Primase Subunit 1 (PRIM1) that synthesizes Okazaki RNA primers. Functionally, demonstrate serves as an anchor for recruiting Histone Deacetylase (HDAC1) to facilitate H4K16 deacetylation R-loop homeostasis maintain stability. Collectively, our data reveal fine-tuning provide arsenal targeting tumors. most cancer. authors non-canonical response. They also lethal such WEE1, can be therapeutically harnessed immediate applicability.
Язык: Английский
Процитировано
1