2. Academic Validation
  3. Human nuclear RNAi-defective 2 (NRDE2) is an essential RNA splicing factor

Human nuclear RNAi-defective 2 (NRDE2) is an essential RNA splicing factor

  • RNA. 2019 Mar;25(3):352-363. doi: 10.1261/rna.069773.118.
Alan L Jiao 1 2,  Roberto Perales 3,  Neil T Umbreit 4,  Jeffrey R Haswell 1 5,  Mary E Piper 6,  Brian D Adams 1,  David Pellman 4 7 8,  Scott Kennedy 3,  Frank J Slack 9
Affiliations

Affiliations

  • 1 HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
  • 2 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
  • 3 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 4 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 5 Department of Biological and Biomedical Sciences, Harvard University, Boston, Massachusetts 02115, USA.
  • 6 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
  • 7 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02215, USA.
  • 8 Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
  • 9 HMS Initiative for RNA Medicine, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [email protected].
PMID: 30538148 DOI: 10.1261/rna.069773.118
Abstract

The accurate inheritance of genetic material is a basic necessity in all domains of life and an unexpectedly large number of RNA processing factors are required for mitotic progression and genome stability. NRDE2 (nuclear RNAi defective-2) is an evolutionarily conserved protein originally discovered for its role in nuclear RNA interference (RNAi) and heritable gene silencing in Caenorhabditis elegans (C. elegans). The function of the human NRDE2 gene remains poorly understood. Here we show that human NRDE2 is an essential protein required for suppressing intron retention in a subset of pre-mRNAs containing short, GC-rich introns with relatively weak 5' and 3' splice sites. NRDE2 preferentially interacts with components of the U5 small nuclear ribonucleoprotein (snRNP), the exon junction complex, and the RNA exosome. Interestingly, NRDE2-depleted cells exhibit greatly increased levels of genomic instability and DNA damage, as well as defects in centrosome maturation and mitotic progression. We identify the essential centriolar satellite protein, CEP131, as a direct NRDE2-regulated target. NRDE2 specifically binds to and promotes the efficient splicing of CEP131 pre-mRNA, and depleting NRDE2 dramatically reduces CEP131 protein expression, contributing to impaired recruitment of critical centrosomal proteins (e.g., γ-tubulin and Aurora Kinase A) to the spindle poles during mitosis. Our work establishes a conserved role for human NRDE2 in RNA splicing, characterizes the severe genomic instability phenotypes observed upon loss of NRDE2, and highlights the direct regulation of CEP131 splicing as one of multiple mechanisms through which such phenotypes might be explained.

Keywords

centrosome; genome stability; intron retention; mitosis; nuclear RNAi; splicing.

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