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The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis

Author

Listed:
  • Mehdi Pirouz

    (Boston Children’s Hospital
    Harvard Medical School
    Manton Center for Orphan Disease Research)

  • Chih-Hao Wang

    (Harvard Medical School)

  • Qi Liu

    (Boston Children’s Hospital
    Harvard Medical School)

  • Aref G. Ebrahimi

    (Harvard Medical School)

  • Farnaz Shamsi

    (Harvard Medical School)

  • Yu-Hua Tseng

    (Harvard Medical School
    Harvard Stem Cell Institute)

  • Richard I. Gregory

    (Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute
    Harvard Medical School)

Abstract

DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs (ncRNAs) including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and RMRP. While mutations in DIS3L2 are associated with Perlman syndrome, the biological significance of impaired DMD is obscure and pathological RNAs have not been identified. Here, by ribosome profiling (Ribo-seq) we find specific dysregulation of endoplasmic reticulum (ER)-targeted mRNA translation in DIS3L2-deficient cells. Mechanistically, DMD functions in the quality control of the 7SL ncRNA component of the signal recognition particle (SRP) required for ER-targeted translation. Upon DIS3L2 loss, sustained 3’-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage. Consequently, elevated intracellular calcium in DIS3L2-deficient cells activates calcium signaling response genes and perturbs ESC differentiation. Thus, DMD is required to safeguard ER-targeted mRNA translation, intracellular calcium homeostasis, and stem cell differentiation.

Suggested Citation

  • Mehdi Pirouz & Chih-Hao Wang & Qi Liu & Aref G. Ebrahimi & Farnaz Shamsi & Yu-Hua Tseng & Richard I. Gregory, 2020. "The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16418-y
    DOI: 10.1038/s41467-020-16418-y
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