RBMX enables productive RNA processing of ultra-long exons important for genome stability

AbstractPreviously we showed that the germline-specific RNA binding protein RBMXL2 is essential for male meiosis where it represses cryptic splicing patterns (1). Here we find that its ubiquitously expressed paralog RBMX helps underpin human genome stability by preventing non-productive splicing. In particular, RBMX blocks selection of aberrant splice and polyadenylation sites within some ultra-long exons that would interfere with genes needed for normal replication fork activity. Target exons include within the ETAA1 (Ewings Tumour Associated 1) gene, where RBMX collaborates with its interaction partner Tra2β to enable full-length exon inclusion by blocking selection of an aberrant 3’ splice site. Our data reveal a novel group of RNA processing targets potently repressed by RBMX, and help explain why RBMX is associated with gene expression networks in cancer, replication and sensitivity to genotoxic drugs.

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An ancient germ cell-specific RNA-binding protein protects the germline from cryptic splice site poisoning

eLife ◽

10.7554/elife.39304 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 5

Author(s):

Ingrid Ehrmann ◽

James H Crichton ◽

Matthew R Gazzara ◽

Katherine James ◽

Yilei Liu ◽

...

Keyword(s):

Germ Cell ◽

Splice Site ◽

Cell Biology ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Aberrant Splice ◽

Splice Site Selection ◽

Ambient Concentrations ◽

Splicing Patterns

Male germ cells of all placental mammals express an ancient nuclear RNA binding protein of unknown function called RBMXL2. Here we find that deletion of the retrogene encoding RBMXL2 blocks spermatogenesis. Transcriptome analyses of age-matched deletion mice show that RBMXL2 controls splicing patterns during meiosis. In particular, RBMXL2 represses the selection of aberrant splice sites and the insertion of cryptic and premature terminal exons. Our data suggest a Rbmxl2 retrogene has been conserved across mammals as part of a splicing control mechanism that is fundamentally important to germ cell biology. We propose that this mechanism is essential to meiosis because it buffers the high ambient concentrations of splicing activators, thereby preventing poisoning of key transcripts and disruption to gene expression by aberrant splice site selection.

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PARP-1–dependent recruitment of cold-inducible RNA-binding protein promotes double-strand break repair and genome stability

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713912115 ◽

2018 ◽

Vol 115 (8) ◽

pp. E1759-E1768 ◽

Cited By ~ 14

Author(s):

Jung-Kuei Chen ◽

Wen-Ling Lin ◽

Zhang Chen ◽

Hung-wen Liu

Keyword(s):

Dna Damage ◽

Genome Stability ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Strand Break ◽

Double Strand Break ◽

Dsb Repair ◽

Active Involvement ◽

Parp 1

Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases. In the absence of CIRBP, cells showed reduced γH2AX, Rad51, and 53BP1 foci formation. Moreover, CIRBP-depleted cells exhibited impaired homologous recombination, impaired nonhomologous end-joining, increased micronuclei formation, and higher sensitivity to gamma irradiation, demonstrating the active involvement of CIRBP in DSB repair. Furthermore, CIRBP depleted cells exhibited defects in DNA damage-induced chromatin association of the MRN complex (Mre11, Rad50, and NBS1) and ATM kinase. CIRBP depletion also reduced phosphorylation of a variety of ATM substrate proteins and thus impaired the DNA damage response. Taken together, these results reveal a previously unrecognized role for CIRBP in DSB repair.

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Human cytomegalovirus induces and exploits Roquin to counteract the IRF1-mediated antiviral state

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909314116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18619-18628 ◽

Cited By ~ 2

Author(s):

Jaewon Song ◽

Sanghyun Lee ◽

Dong-Yeon Cho ◽

Sungwon Lee ◽

Hyewon Kim ◽

...

Keyword(s):

Human Cytomegalovirus ◽

Rna Processing ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Transcriptome Profiling ◽

Loss Of Function ◽

Antiviral Genes ◽

Cellular Antiviral Response ◽

Infected Cells

RNA represents a pivotal component of host–pathogen interactions. Human cytomegalovirus (HCMV) infection causes extensive alteration in host RNA metabolism, but the functional relationship between the virus and cellular RNA processing remains largely unknown. Through loss-of-function screening, we show that HCMV requires multiple RNA-processing machineries for efficient viral lytic production. In particular, the cellular RNA-binding protein Roquin, whose expression is actively stimulated by HCMV, plays an essential role in inhibiting the innate immune response. Transcriptome profiling revealed Roquin-dependent global down-regulation of proinflammatory cytokines and antiviral genes in HCMV-infected cells. Furthermore, using cross-linking immunoprecipitation (CLIP)-sequencing (seq), we identified IFN regulatory factor 1 (IRF1), a master transcriptional activator of immune responses, as a Roquin target gene. Roquin reduces IRF1 expression by directly binding to its mRNA, thereby enabling suppression of a variety of antiviral genes. This study demonstrates how HCMV exploits host RNA-binding protein to prevent a cellular antiviral response and offers mechanistic insight into the potential development of CMV therapeutics.

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Transcriptome-Wide Identification of RNA Targets of Arabidopsis SERINE/ARGININE-RICH45 Uncovers the Unexpected Roles of This RNA Binding Protein in RNA Processing

The Plant Cell ◽

10.1105/tpc.15.00641 ◽

2015 ◽

Vol 27 (12) ◽

pp. 3294-3308 ◽

Cited By ~ 49

Author(s):

Denghui Xing ◽

Yajun Wang ◽

Michael Hamilton ◽

Asa Ben-Hur ◽

Anireddy S.N. Reddy

Keyword(s):

Rna Processing ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Rna Targets

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Abstract 204: Molecular function of the RNA binding protein EWS in RNA processing

10.1158/1538-7445.am2012-204 ◽

2012 ◽

Author(s):

Bethsaida I. Nieves ◽

Shuang Niu ◽

Dedeepya Vaka ◽

Julia Salzman ◽

Patrick Brown ◽

...

Keyword(s):

Rna Processing ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Molecular Function

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The Nuclear RNA-binding Protein Sam68 Translocates to the Cytoplasm and Associates with the Polysomes in Mouse Spermatocytes

Molecular Biology of the Cell ◽

10.1091/mbc.e05-06-0548 ◽

2006 ◽

Vol 17 (1) ◽

pp. 14-24 ◽

Cited By ~ 60

Author(s):

Maria Paola Paronetto ◽

Francesca Zalfa ◽

Flavia Botti ◽

Raffaele Geremia ◽

Claudia Bagni ◽

...

Keyword(s):

Translational Control ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Male Meiosis ◽

Binding Motif ◽

Mitogen Activated Protein ◽

Pachytene Spermatocytes ◽

And Function

Translational control plays a crucial role during gametogenesis in organisms as different as worms and mammals. Mouse knockout models have highlighted the essential function of many RNA-binding proteins during spermatogenesis. Herein we have investigated the expression and function during mammalian male meiosis of Sam68, an RNA-binding protein implicated in several aspects of RNA metabolism. Sam68 expression and localization within the cells is stage specific: it is expressed in the nucleus of spermatogonia, it disappears at the onset of meiosis (leptotene/zygotene stages), and it accumulates again in the nucleus of pachytene spermatocytes and round spermatids. During the meiotic divisions, Sam68 translocates to the cytoplasm where it is found associated with the polysomes. Translocation correlates with serine/threonine phosphorylation and it is blocked by inhibitors of the mitogen activated protein kinases ERK1/2 and of the maturation promoting factor cyclinB-cdc2 complex. Both kinases associate with Sam68 in pachytene spermatocytes and phosphorylate the regulatory regions upstream and downstream of the Sam68 RNA-binding motif. Molecular cloning of the mRNAs associated with Sam68 in mouse spermatocytes reveals a subset of genes that might be posttranscriptionally regulated by this RNA-binding protein during spermatogenesis. We also demonstrate that Sam68 shuttles between the nucleus and the cytoplasm in secondary spermatocytes, suggesting that it may promote translation of specific RNA targets during the meiotic divisions.

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