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.
Highlights
DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs including ribosomal RNAs, transfer RNAs, small nuclear RNAs, and RNA component of mitochondrial RNA processing (RMRP)
Altered translation of many messenger RNAs (mRNAs) was detected by changes in the abundance of ribosomeprotected fragments (RPFs) (Fig. 1a, Supplementary Fig. 1a, and Supplementary Data 1)
For the translationally downregulated mRNAs, we observed decreased RPFs throughout the coding regions (CDS) of the mRNAs, yet interestingly, we noticed a specific accumulation of RPFs at the 5′ end of the respective CDS (Fig. 1d), consistent with the observation that signal peptides are typically contained at the termini of respective proteins[48]
Summary
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. DIS3L2-mediated decay (DMD) was recently identified as a surveillance pathway for certain ncRNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), microRNAs (miRNAs), and RNA component of mitochondrial RNA processing (RMRP)[1,2,3,4,5,6,7,8,9,10,11,12,13]. These aberrant ncRNAs are oligouridylated by the terminal uridyl transferases (TUTases) TUT4 ( known as ZCCHC11, and TENT3A) and TUT7 (ZCCHC6, or TENT3B), and subsequently degraded by the 3′–5′ exoribonuclease DIS3L2. Embryonic stem cell (ESC) differentiation including that towards the renal lineage is perturbed, reminiscent of the renal abnormalities in Perlman syndrome patients[20]
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