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Nuclear TARBP2 Drives Oncogenic Dysregulation of RNA Splicing and Decay

Lisa Fish1, Albertas Navickas1, Bruce Culbertson1

  • 1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.

Molecular Cell
|July 14, 2019
PubMed

Insights

The RNA binding protein TARBP2 controls gene expression by destabilizing RNA transcripts in the nucleus. This mechanism plays a role in lung cancer progression and involves m6A RNA methylation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Cancer Biology

Background:

  • Post-transcriptional regulation of RNA stability is crucial for controlling gene expression.
  • RNA binding proteins play significant roles in modulating RNA fate.
  • The nuclear exosome is a key component of RNA degradation pathways.

Purpose of the Study:

  • To elucidate the regulatory program mediated by TARBP2 in controlling nuclear RNA stability.
  • To investigate the role of TARBP2 in lung cancer.
  • To identify upstream regulators of TARBP2.

Main Methods:

  • Investigated TARBP2-mediated RNA binding and its effect on pre-mRNA processing (intron retention).
  • Examined the recruitment of the m6A RNA methylation machinery and its impact on splicing.
  • Studied the interaction of TARBP2 with TPR and the nuclear exosome for transcript degradation.
  • Analyzed clinical gene expression datasets and utilized xenograft mouse models for lung cancer studies.

Main Results:

  • TARBP2 binding to pre-mRNAs increases intron retention, leading to transcript degradation via the nuclear exosome.
  • TARBP2 recruits the m6A RNA methylation machinery, which inhibits splicing by affecting splicing regulator recruitment.
  • TARBP2 promotes the degradation of its target transcripts through interaction with TPR and the nuclear exosome.
  • TARBP2 significantly impacts lung tumor growth by destabilizing ABCA3 and FOXN3 transcripts.
  • ZNF143 was identified as an upstream regulator of TARBP2 expression.

Conclusions:

  • TARBP2 mediates a nuclear RNA decay pathway involving intron retention and m6A methylation, impacting gene expression.
  • TARBP2 plays a critical role in lung cancer progression through the destabilization of specific target genes.
  • ZNF143 acts as an upstream regulator controlling TARBP2 expression, highlighting a novel regulatory axis.
Keywords:
TARBP2breast cancerintron retentionlung cancerm(6)Ametastasisnuclear RNA decaypost-transcriptional regulationsplicing regulation

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