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1.
Mol Cell ; 83(12): 1983-2002.e11, 2023 Jun 15.
Article in English | MEDLINE | ID: mdl-37295433

ABSTRACT

The evolutionarily conserved minor spliceosome (MiS) is required for protein expression of ∼714 minor intron-containing genes (MIGs) crucial for cell-cycle regulation, DNA repair, and MAP-kinase signaling. We explored the role of MIGs and MiS in cancer, taking prostate cancer (PCa) as an exemplar. Both androgen receptor signaling and elevated levels of U6atac, a MiS small nuclear RNA, regulate MiS activity, which is highest in advanced metastatic PCa. siU6atac-mediated MiS inhibition in PCa in vitro model systems resulted in aberrant minor intron splicing leading to cell-cycle G1 arrest. Small interfering RNA knocking down U6atac was ∼50% more efficient in lowering tumor burden in models of advanced therapy-resistant PCa compared with standard antiandrogen therapy. In lethal PCa, siU6atac disrupted the splicing of a crucial lineage dependency factor, the RE1-silencing factor (REST). Taken together, we have nominated MiS as a vulnerability for lethal PCa and potentially other cancers.


Subject(s)
Prostatic Neoplasms, Castration-Resistant , Prostatic Neoplasms , Male , Humans , Introns/genetics , Prostatic Neoplasms/metabolism , RNA Splicing/genetics , Spliceosomes/metabolism , Signal Transduction , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Cell Line, Tumor , Prostatic Neoplasms, Castration-Resistant/genetics
2.
Development ; 148(20)2021 10 15.
Article in English | MEDLINE | ID: mdl-34557915

ABSTRACT

Minor spliceosome inhibition due to mutations in RNU4ATAC are linked to primary microcephaly. Ablation of Rnu11, which encodes a minor spliceosome snRNA, inhibits the minor spliceosome in the developing mouse pallium, causing microcephaly. There, cell cycle defects and p53-mediated apoptosis in response to DNA damage resulted in loss of radial glial cells (RGCs), underpinning microcephaly. Here, we ablated Trp53 to block cell death in Rnu11 cKO mice. We report that Trp53 ablation failed to prevent microcephaly in these double knockout (dKO) mice. We show that the transcriptome of the dKO pallium was more similar to the control compared with the Rnu11 cKO. We find aberrant minor intron splicing in minor intron-containing genes involved in cell cycle regulation, resulting in more severely impaired mitotic progression and cell cycle lengthening of RGCs in the dKO that was detected earlier than in the Rnu11 cKO. Furthermore, we discover a potential role of p53 in causing DNA damage in the developing pallium, as detection of γH2aX+ was delayed in the dKO. Thus, we postulate that microcephaly in minor spliceosome-related diseases is primarily caused by cell cycle defects.


Subject(s)
Introns/genetics , Microcephaly/genetics , RNA Splicing/genetics , Tumor Suppressor Protein p53/genetics , Animals , Cell Cycle/genetics , Cell Death/genetics , Ependymoglial Cells/pathology , Female , Male , Mice , Mice, Knockout , Mutation/genetics , RNA, Small Nuclear/genetics , Spliceosomes/genetics , Transcriptome/genetics
3.
Development ; 147(21)2020 08 14.
Article in English | MEDLINE | ID: mdl-32665241

ABSTRACT

Disruption of the minor spliceosome due to mutations in RNU4ATAC is linked to primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1, Roifman syndrome, and Lowry-Wood syndrome. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite being vital for limb development and size regulation, its role remains unexplored. Here, we disrupt minor spliceosome function in the developing mouse limb by ablating one of its essential components, U11 small nuclear RNA, which resulted in micromelia. Notably, earlier loss of U11 corresponded to increased severity. We find that limb size is reduced owing to elevated minor intron retention in minor intron-containing genes that regulate cell cycle. As a result, limb progenitor cells experience delayed prometaphase-to-metaphase transition and prolonged S-phase. Moreover, we observed death of rapidly dividing, distally located progenitors. Despite cell cycle defects and cell death, the spatial expression of key limb patterning genes was maintained. Overall, we show that the minor spliceosome is required for limb development via size control potentially shared in disease and domestication.


Subject(s)
Dwarfism/genetics , Extremities/embryology , Fetal Growth Retardation/genetics , Microcephaly/genetics , Osteochondrodysplasias/genetics , RNA, Small Nuclear/metabolism , Animals , Body Patterning/genetics , Cell Cycle/genetics , Female , Forelimb/embryology , Forelimb/ultrastructure , Gene Expression Regulation, Developmental , Hindlimb/embryology , Hindlimb/ultrastructure , Introns/genetics , Male , Mice, Inbred C57BL , Mutation/genetics , RNA, Small Nuclear/genetics , Stem Cells/metabolism
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