N6-methyladenosine (m6A) modification of ribosomal RNAs (rRNAs): Critical roles in mRNA translation and diseases

Abstract

As key components of the ribosome and the most abundant RNA species, the rRNAs are modified during ribosome formation. N⁶-methyladenosine (m⁶A) is a conserved RNA modification occurring on different RNA species including rRNAs. Recently, it has been reported that ZCCHC4 and METTL5 are methyltransferases that mediate m⁶A modification of human 28S and 18S rRNA, respectively. The newly discovered biological functions of the two methyltransferases include regulation of mRNA translation, cell proliferation, cell differentiation, stress response, and other biological processes. Both of them, especially METTL5, have been proved to be associated with a variety of diseases such as intellectual disability, cancer, congenital dysplasia and have potential clinical application as biomarkers and therapeutic targets.

Keywords: Biological processes; Diseases; METTL5; ZCCHC4; m6A.

Figure 1

The multi-copy structure of rDNA in humans and mice. Adapted from references 3 and 4. The rRNA genes encoding 18S, 5.8S and 28S exist as tandem repeats on five pairs of chromosomes (the 5S rDNA is on the chromosome 1 in humans and chromosome 8 in mice). A single repeat (43 kb in humans and 45 kb in mice) can be divided into the ribosomal part and the intergenic sequence (IGS). The ribosomal part (13 kb in human and 15 kb in mouse) flanked by external spacers (5′ ETS and 3′ETS) contains three genes separated by internal transcribed spacers (ITS1 and ITS2). The IGS part is a complex with highly repetitive sequences and even more variant than rDNA.

Figure 2

The functional domains and enzymic activity of ZCCHC4 and METTL5. (A) Schematic representation of functional domains of ZCCHC4 and TRMT112-METTL5 complex. (B) ZCCHC4 and METTL5 mediated the methylation of 28S rRNA m⁶A4220 and 18S rRNA m⁶A1832, respectively, by adding a methyl group to the sixth nitrogen atom of adenine. Previous studies have shown that m⁶A is a reversible modification process, but the demethylase responsible for rRNA demethylation has not been identified.

Figure 3

Ribosome stress leads to the disorder of p53-MDM2 negative feedback loop and a series of diseases. p53 and MDM2 form a negative feedback loop under normal circumstances. When abnormal ribosome synthesis leads to ribosome stress, ribosome associated proteins will bind to MDM2, bringing to p53 accumulation and cell apoptosis, which leads to a series of diseases classified into ribosomopathies or neurocristopathies.