RES complex is associated with intron definition and required for zebrafish early embryogenesis

Fernández, Juan Pablo; Moreno-Mateos, Miguel A.; Gohr, André; Miao, Liyun; Chan, Shun Hang; Irimia, Manuel; Giráldez, Antonio J.

doi:10.1371/journal.pgen.1007473

Cited by 23 publications

(16 citation statements)

References 64 publications

(80 reference statements)

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“…The list of 202 SFs used in this study was derived from a published list of known SFs in mice [ 69 ] for which 1:1 orthologs could be identified in humans, plus 6 manual additions of human genes with evidence of SF activity or family members thereof: ARGLU1 [ 70 ], PCBP2 [ 71 ], PRPF18 [ 72 ], SNIP1 [ 73 ], SRRM3 [ 22 ], and SFRS2 [ 74 ]. The complete list can be found in S1 Data .…”

Section: Methodsmentioning

confidence: 99%

Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers

et al. 2021

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RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3–27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.

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Section: Methodsmentioning

confidence: 99%

Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers

et al. 2021

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“…In higher metazoa (vertebrata in particular) 5′- and 3′ splice sites in the primary transcript are initially paired across each exon (“exon definition”), enabling the existence of large introns alternating with much smaller exons 19,20 . Nevertheless, short introns exist in, e.g., Drosophila melanogaster 21 and zebrafish 22 and their proper excision is preceded by interactions across the intron (“intron definition”). Moreover, the canonical U2 units of complex intervening sequences in higher metazoa (abutted U2 introns; nested U2 introns) 9,10,12,13 are subject to intron defining interactions.…”

Section: Introductionmentioning

confidence: 99%

A spliceosomal twin intron (stwintron) participates in both exon skipping and evolutionary exon loss

Kavalecz

Fekete

Karaffa

et al. 2019

Sci Rep

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Spliceosomal twin introns (stwintrons) are introns where any of the three consensus sequences involved in splicing is interrupted by another intron (internal intron). In Aspergillus nidulans , a donor-disrupted stwintron (intron-1) is extant in the transcript encoding a reticulon-like protein. The orthologous transcript of Aspergillus niger can be alternatively spliced; the exon downstream the stwintron could be skipped by excising a sequence that comprises this stwintron, the neighbouring intron-2, and the exon bounded by these. This process involves the use of alternative 3′ splice sites for the internal intron, the resulting alternative intervening sequence being a longer 3′-extended stwintron. In 29 species of Onygenales , a multi-step splicing process occurs in the orthologous transcript, in which a complex intervening sequence including the stwintron and neigbouring intron-2, generates by three splicing reactions a “second order intron” which must then be excised with a fourth splicing event. The gene model in two species can be envisaged as one canonical intron (intron-1) evolved from this complex intervening sequence of nested canonical introns found elsewhere in Onygenales . Postulated splicing intermediates were experimentally verified in one or more species. This work illustrates a role of stwintrons in both alternative splicing and the evolution of intron structure.

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“…However, introncontaining IRF7 mRNA could not be detected in the cytoplasm (37), indicating additional nuclear trapping mechanisms or rapid cytoplasmic degradation of intron-containing IRF7 mRNA. HIV-1 introns also differ from typical RES-dependent introns (37)(38)(39) by their low GC content, challenging the hypothesis that HIV-1 splicing may be regulated by the RES.…”

mentioning

confidence: 98%

CRNKL1 Is a Highly Selective Regulator of Intron-Retaining HIV-1 and Cellular mRNAs

Han

Wyler

Milek

et al. 2021

mBio

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The HIV-1 Rev protein is a nuclear export factor for unspliced and incompletely spliced HIV-1 RNAs. Without Rev, these intron-retaining RNAs are trapped in the nucleus. A genome-wide screen identified nine proteins of the spliceosome, which all enhanced expression from the HIV-1 unspliced RNA after CRISPR/Cas knockdown. Depletion of DHX38, WDR70, and four proteins of the Prp19-associated complex (ISY1, BUD31, XAB2, and CRNKL1) resulted in a more than 20-fold enhancement of unspliced HIV-1 RNA levels in the cytoplasm. Targeting of CRNKL1, DHX38, and BUD31 affected nuclear export efficiencies of the HIV-1 unspliced RNA to a much larger extent than splicing. Transcriptomic analyses further revealed that CRNKL1 also suppresses cytoplasmic levels of a subset of cellular mRNAs, including some with selectively retained introns. Thus, CRNKL1-dependent nuclear retention is a novel cellular mechanism for the regulation of cytoplasmic levels of intron-retaining HIV-1 mRNAs, which HIV-1 may have harnessed to direct its complex splicing pattern. IMPORTANCE To regulate its complex splicing pattern, HIV-1 uses the adaptor protein Rev to shuttle unspliced or partially spliced mRNA from the nucleus to the cytoplasm. In the absence of Rev, these RNAs are retained in the nucleus, but it is unclear why. Here we identify cellular proteins whose depletion enhances cytoplasmic levels of the HIV-1 unspliced RNA. Depletion of one of them, CRNKL1, also increases cytoplasmic levels of a subset of intron-retaining cellular mRNA, suggesting that CRNKL1-dependent nuclear retention may be a basic cellular mechanism exploited by HIV-1.

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RES complex is associated with intron definition and required for zebrafish early embryogenesis

Cited by 23 publications

References 64 publications

Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers

Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers

A spliceosomal twin intron (stwintron) participates in both exon skipping and evolutionary exon loss

CRNKL1 Is a Highly Selective Regulator of Intron-Retaining HIV-1 and Cellular mRNAs

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