Author: Smart, Alfredo D ; Heatley, Matthew C ; Downie Ruiz Velasco, Angela ; Parsons, Aimee L ; Shah, Niraj ; Jopling, Catherine L ; Martin, Athena R G

AbstractIn animals, microRNA (miRNA) biogenesis begins with cotranscriptional cleavage of the primary (pri-)miRNA by the Microprocessor complex. Cotranscriptional splicing has been shown to influence Microprocessor cleavage when miRNAs are hosted in introns of protein-coding pri-miRNAs, but the impact of splicing on production of miRNAs hosted in long non-coding (lnc)RNAs is largely unknown. Here, we investigated the role of splicing in the biogenesis of miR-122, an lncRNA-hosted, highly expressed, medically important, liver-specific miRNA. We found that splicing inhibition by the SF3B1 inhibitor pladienolide B (PlaB) led to strong and rapid reduction in transcription of endogenous, but not plasmid-encoded, pri-miR-122, resulting in reduced production of mature miR-122. To allow detection of rapid changes in miRNA biogenesis despite the high stability of mature miRNAs, we used SLAMseq to globally quantify the effects of short-term splicing inhibition on miRNA synthesis. We observed an overall decrease in biogenesis of mature miRNAs following PlaB treatment. Surprisingly, miRNAs hosted in exons and introns were similarly affected. Together, this study provides new insights into the emerging role of splicing in transcription, demonstrating novel biological importance in promotion of miR-122 biogenesis from an lncRNA, and shows that SF3B1 is important for global miRNA biogenesis.

01 Jun 2024·Molecular Therapy - Nucleic Acids

Aberrant spliceosome activity via elevated intron retention and upregulation and phosphorylation of SF3B1 in chronic lymphocytic leukemia

Article

Author: Moreno, Eider ; Mariño-Ramírez, Leonardo ; Kashyap, Manoj Kumar ; Kipps, Thomas J ; Vidal, Newton Medeiros ; Kumar, Deepak ; Karathia, Hiren ; Mount, Stephen M ; Achinko, Daniel ; Lengerke-Diaz, Paula A ; Yu, Zhe ; Vera Alvarez, Roberto ; Ghia, Emanuela M ; Hannenhalli, Sridhar ; Lujan, Juliana Velez ; Forero-Forero, Jose Vicente ; Castro, Januario E ; Choi, Michael Y ; Rassenti, Laura Z ; Amaya-Chanaga, Carlos Ivan

Splicing factor 3b subunit 1 (SF3B1) is the largest subunit and core component of the spliceosome. Inhibition of SF3B1 was associated with an increase in broad intron retention (IR) on most transcripts, suggesting that IR can be used as a marker of spliceosome inhibition in chronic lymphocytic leukemia (CLL) cells. Furthermore, we separately analyzed exonic and intronic mapped reads on annotated RNA-sequencing transcripts obtained from B cells (n = 98 CLL patients) and healthy volunteers (n = 9). We measured intron/exon ratio to use that as a surrogate for alternative RNA splicing (ARS) and found that 66% of CLL-B cell transcripts had significant IR elevation compared with normal B cells (NBCs) and that correlated with mRNA downregulation and low expression levels. Transcripts with the highest IR levels belonged to biological pathways associated with gene expression and RNA splicing. A >2-fold increase of active pSF3B1 was observed in CLL-B cells compared with NBCs. Additionally, when the CLL-B cells were treated with macrolides (pladienolide-B), a significant decrease in pSF3B1, but not total SF3B1 protein, was observed. These findings suggest that IR/ARS is increased in CLL, which is associated with SF3B1 phosphorylation and susceptibility to SF3B1 inhibitors. These data provide additional support to the relevance of ARS in carcinogenesis and evidence of pSF3B1 participation in this process.

21 Jan 2022·Science AdvancesQ1 · CROSS-FIELD

SF3B1 homeostasis is critical for survival and therapeutic response in T cell leukemia

Q1 · CROSS-FIELD

ArticleOA

Author: Lorch, Adam H. ; Cho, Byoung-Kyu ; Obeng, Rebecca C. ; Zhou, Yalu ; Zhu, Ping ; Basso, Giuseppe ; Velu, Sadanandan E. ; Jin, Qi ; Goo, Young Ah ; Serafin, Valentina ; Buldini, Barbara ; Politanska, Yuliya ; Pryzhkova, Marina V. ; Abdala-Valencia, Hiam ; Sarma, Kavitha ; Ntziachristos, Panagiotis ; Bartom, Elizabeth Thomas ; Han, Cuijuan ; Mattamana, Basil B. ; Gutierrez-Diaz, Blanca T. ; Tsirigos, Aristotelis ; Khodadadi-Jamayran, Alireza ; Jordan, Philip W. ; Sun, Limin

The production of noncanonical mRNA transcripts is associated with cell transformation. Driven by our previous findings on the sensitivity of T cell acute lymphoblastic leukemia (T-ALL) cells to SF3B1 inhibitors, we identified that SF3B1 inhibition blocks T-ALL growth in vivo with no notable associated toxicity. We also revealed protein stabilization of the U2 complex component SF3B1 via deubiquitination. Our studies showed that SF3B1 inhibition perturbs exon skipping, leading to nonsense-mediated decay and diminished levels of DNA damage response–related transcripts, such as the serine/threonine kinase CHEK2 , and impaired DNA damage response. We also identified that SF3B1 inhibition leads to a general decrease in R-loop formation. We further demonstrate that clinically used SF3B1 inhibitors synergize with CHEK2 inhibitors and chemotherapeutic drugs to block leukemia growth. Our study provides the proof of principle for posttranslational regulation of splicing components and associated roles and therapeutic implications for the U2 complex in T cell leukemia.

100 Deals associated with FR-901464 analogs (SRI)

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	US	Stanford Cancer Institute	-
Breast Cancer	Preclinical	US	SRI International	-
Chronic Lymphocytic Leukemia	Preclinical	US	SRI International	-

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