Cellular RNA surveillance in health and disease

Abstract

The numerous quality control pathways that target defective ribonucleic acids (RNAs) for degradation play key roles in shaping mammalian transcriptomes and preventing disease. These pathways monitor most steps in the biogenesis of both noncoding RNAs (ncRNAs) and protein-coding messenger RNAs (mRNAs), degrading ncRNAs that fail to form functional complexes with one or more proteins and eliminating mRNAs that encode abnormal, potentially toxic proteins. Mutations in components of diverse RNA surveillance pathways manifest as disease. Some mutations are characterized by increased interferon production, suggesting that a major role of these pathways is to prevent aberrant cellular RNAs from being recognized as "non-self." Other mutations are common in cancer, or result in developmental defects, revealing the importance of RNA surveillance to cell and organismal function.

Fig. 1. Protein adaptors target aberrant RNAs for degradation

(A) In the nucleus, NEXT (top left) targets newly synthesized RNA polymerase II-transcribed poly(A)⁻ ncRNAs and pre-mRNAs for degradation by the RNA exosome, while MTR4-ZFC3H1 (top right) targets nascent RNA polymerase II-transcribed poly(A)⁺ ncRNAs and poly(A)⁺ pre-mRNAs for exosome degradation. Prematurely terminated pre-rRNA precursors, as well as some RNA polymerase II- and polymerase III-transcribed ncRNA precursors, are adenylated by the TENT4B-ZCCHC7-MTR4 complex (bottom), facilitating degradation by the RNA exosome. (B) In the cytoplasm, TUT4 (left) and TUT7 (right) add a short U tail to defective ncRNA precursors, stimulating degradation by the DIS3L2 exoribonuclease.

Fig. 2. Nuclear synthesis and surveillance of protein-coding transcripts

Following transcription, pre-mRNA splicing, EJC deposition and 3′-end formation, mRNAs are subject to quality control at the nuclear pore. Upon export, ribosomes engaged in the pioneer round of translation remove EJCs in their path, the CBC is replaced by eIF4E and PABPN1 is replaced by the cytoplasmic poly(A) binding protein PABPC1.

Fig. 3. Cytoplasmic surveillance of protein-coding transcripts

(A) If the ribosome terminates before reaching the final EJC, the NMD machinery interacts with the EJC and targets the mRNA for degradation. (B) In no-go and possibly nonstop decay, a ribosome stalls during translation elongation. As a consequence, ribosomes collide, providing a surface for ubiquitination by ZNF598. Afterwards, the N4BP2/Cue2 endonuclease cleaves at the 5′ side of the stalled ribosome, allowing rescue and recycling by PELO and HBS1.

Fig. 4. Surveillance of dsRNA

(A) In the cytoplasm, ADAR1 deaminates adenines in dsRNA to inosine, disrupting base-pairing. RNAs that fail to undergo editing can activate MDA5 and PKR. (B) Formation of mitochondrial dsRNA is normally prevented by PNPT1, which degrades the antisense RNA. Under stress, or when PNPT1 is mutated, mitochondrial dsRNAs can enter the cytosol and activate MDA5 and PKR.