Disruption of the Caenorhabditis Elegans Integrator Complex Triggers a Non-conventional Transcriptional Mechanism Beyond SnRNA Genes

Overview

Journal PLoS Genet

Specialty Genetics

Date 2019 Feb 27

PMID 30807579

Citations 26

Authors

Eva Gomez-Orte

Beatriz Saenz-Narciso

Angelina Zheleva

Begona Ezcurra

Maria de Toro

Rosario Lopez

Irene Gastaca

Hilde Nilsen

Maria P Sacristan

Ralf Schnabel

Juan Cabello

Affiliations

Soon will be listed here.

Abstract

Gene expression is generally regulated by recruitment of transcription factors and RNA polymerase II (RNAP II) to specific sequences in the gene promoter region. The Integrator complex mediates processing of small nuclear RNAs (snRNAs) as well as the initiation and release of paused RNAP II at specific genes in response to growth factors. Here we show that in C. elegans, disruption of the Integrator complex leads to transcription of genes located downstream of the snRNA loci via a non-conventional transcription mechanism based on the lack of processing of the snRNAs. RNAP II read-through generates long chimeric RNAs containing snRNA, the intergenic region and the mature mRNA of the downstream gene located in sense. These chimeric sn-mRNAs remain as untranslated long non-coding RNAs, in the case of U1- and U2-derived sn-mRNAs, but can be translated to proteins in the case of SL-derived sn-mRNAs. The transcriptional effect caused by disruption of the Integrator complex is not restricted to genes located downstream of the snRNA loci but also affects key regulators of signal transduction such as kinases and phosphatases. Our findings highlight that these transcriptional alterations may be behind the correlation between mutations in the Integrator complex and tumor transformation.

Citing Articles

Integrator complex subunit 6 (INTS-6) mediates DNA damage response in .

Romero-Aranda C, Saenz-Narciso B, Gomez-Orte E, Metola A, Ezcurra B, Calvo O MicroPubl Biol. 2024; 2024.

PMID: 39575199 PMC: 11579701. DOI: 10.17912/micropub.biology.001345.

Unprocessed snRNAs Are a Prognostic Biomarker and Correlate with a Poorer Prognosis in Colorectal Cancer.

Escrich V, Romero-Aranda C, Lopez R, de Toro M, Metola A, Ezcurra B Cancers (Basel). 2024; 16(13).

PMID: 39001402 PMC: 11240374. DOI: 10.3390/cancers16132340.

Automated profiling of gene function during embryonic development.

Green R, Khaliullin R, Zhao Z, Ochoa S, Hendel J, Chow T Cell. 2024; 187(12):3141-3160.e23.

PMID: 38759650 PMC: 11166207. DOI: 10.1016/j.cell.2024.04.012.

A role for the C. elegans Argonaute protein CSR-1 in small nuclear RNA 3' processing.

Waddell B, Wu C PLoS Genet. 2024; 20(5):e1011284.

PMID: 38743783 PMC: 11125478. DOI: 10.1371/journal.pgen.1011284.

Chemical Genetics in Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response.

Abraham E, Athapaththu A, Atanasova K, Chen Q, Corcoran T, Piloto J ACS Chem Biol. 2024; 19(5):1180-1193.

PMID: 38652683 PMC: 11102292. DOI: 10.1021/acschembio.4c00131.

References

Wieland I, Arden K, Michels D, Klein-Hitpass L, Bohm M, Viars C . Isolation of DICE1: a gene frequently affected by LOH and downregulated in lung carcinomas. Oncogene. 1999; 18(32):4530-7. DOI: 10.1038/sj.onc.1202806. View

Wieland I, Ropke A, Stumm M, Sell C, Weidle U, Wieacker P . Molecular characterization of the DICE1 (DDX26) tumor suppressor gene in lung carcinoma cells. Oncol Res. 2002; 12(11-12):491-500. DOI: 10.3727/096504001108747503. View

Callebaut I, Moshous D, Mornon J, de Villartay J . Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family. Nucleic Acids Res. 2002; 30(16):3592-601. PMC: 134238. DOI: 10.1093/nar/gkf470. View

Kamath R, Fraser A, Dong Y, Poulin G, Durbin R, Gotta M . Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature. 2003; 421(6920):231-7. DOI: 10.1038/nature01278. View

Rual J, Ceron J, Koreth J, Hao T, Nicot A, Hirozane-Kishikawa T . Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 2004; 14(10B):2162-8. PMC: 528933. DOI: 10.1101/gr.2505604. View

Dominski Z, Yang X, Purdy M, Wagner E, Marzluff W . A CPSF-73 homologue is required for cell cycle progression but not cell growth and interacts with a protein having features of CPSF-100. Mol Cell Biol. 2005; 25(4):1489-500. PMC: 548002. DOI: 10.1128/MCB.25.4.1489-1500.2005. View

Baillat D, Hakimi M, Naar A, Shilatifard A, Cooch N, Shiekhattar R . Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell. 2005; 123(2):265-76. DOI: 10.1016/j.cell.2005.08.019. View

Han S, Lee T, Mun J, Kim M, Kritikou E, Lee S . Deleted in cancer 1 (DICE1) is an essential protein controlling the topology of the inner mitochondrial membrane in C. elegans. Development. 2006; 133(18):3597-606. DOI: 10.1242/dev.02534. View

Matera A, Terns R, Terns M . Non-coding RNAs: lessons from the small nuclear and small nucleolar RNAs. Nat Rev Mol Cell Biol. 2007; 8(3):209-20. DOI: 10.1038/nrm2124. View

10.

Ljungman M . The transcription stress response. Cell Cycle. 2007; 6(18):2252-7. DOI: 10.4161/cc.6.18.4751. View

11.

Marzluff W, Wagner E, Duronio R . Metabolism and regulation of canonical histone mRNAs: life without a poly(A) tail. Nat Rev Genet. 2008; 9(11):843-54. PMC: 2715827. DOI: 10.1038/nrg2438. View

12.

Frokjaer-Jensen C, Davis M, Hopkins C, Newman B, Thummel J, Olesen S . Single-copy insertion of transgenes in Caenorhabditis elegans. Nat Genet. 2008; 40(11):1375-83. PMC: 2749959. DOI: 10.1038/ng.248. View

13.

Rutkowski R, Warren W . Phenotypic analysis of deflated/Ints7 function in Drosophila development. Dev Dyn. 2009; 238(5):1131-9. DOI: 10.1002/dvdy.21922. View

14.

Anderson M, Jodoin J, Lee E, Hales K, Hays T, Lee L . Asunder is a critical regulator of dynein-dynactin localization during Drosophila spermatogenesis. Mol Biol Cell. 2009; 20(11):2709-21. PMC: 2688550. DOI: 10.1091/mbc.e08-12-1165. View

15.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

16.

Tao S, Cai Y, Sampath K . The Integrator subunits function in hematopoiesis by modulating Smad/BMP signaling. Development. 2009; 136(16):2757-65. DOI: 10.1242/dev.034959. View

17.

Huang J, Gong Z, Ghosal G, Chen J . SOSS complexes participate in the maintenance of genomic stability. Mol Cell. 2009; 35(3):384-93. PMC: 2756616. DOI: 10.1016/j.molcel.2009.06.011. View

18.

Skaar J, Richard D, Saraf A, Toschi A, Bolderson E, Florens L . INTS3 controls the hSSB1-mediated DNA damage response. J Cell Biol. 2009; 187(1):25-32. PMC: 2762097. DOI: 10.1083/jcb.200907026. View

19.

Filleur S, Hirsch J, Wille A, Schon M, Sell C, Shearer M . INTS6/DICE1 inhibits growth of human androgen-independent prostate cancer cells by altering the cell cycle profile and Wnt signaling. Cancer Cell Int. 2009; 9:28. PMC: 2779787. DOI: 10.1186/1475-2867-9-28. View

20.

Robinson M, McCarthy D, Smyth G . edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2009; 26(1):139-40. PMC: 2796818. DOI: 10.1093/bioinformatics/btp616. View