Maturation of mammalian H/ACA box snoRNAs: PAPD5-dependent adenylation and PARN-dependent trimming

Abstract

Small nucleolar and small Cajal body RNAs (snoRNAs and scaRNAs) of the H/ACA box and C/D box type are generated by exonucleolytic shortening of longer precursors. Removal of the last few nucleotides at the 39 end is known to be a distinct step. We report that, in human cells, knock-down of the poly(A) specific ribonuclease (PARN), previously implicated only in mRNA metabolism, causes the accumulation of oligoadenylated processing intermediates of H/ACA box but not C/D box RNAs. In agreement with a role of PARN in snoRNA and scaRNA processing, the enzyme is concentrated in nucleoli and Cajal bodies. Oligo(A) tails are attached to a short stub of intron sequence remaining beyond the mature 39 end of the snoRNAs. The noncanonical poly(A) polymerase PAPD5 is responsible for addition of the oligo(A) tails. We suggest that deadenylation is coupled to clean 39 end trimming, which might serve to enhance snoRNA stability.

Oligoadenylation of 3′ decay intermediates promotes cytoplasmic mRNA degradation in Drosophila cells

“…Nevertheless, cytoplasmic functions have been reported for several Trf4-like enzymes: C. elegans GLD-4 is partially localized in cytoplasmic RNA granules (Schmid et al 2009), sediments with polysomes ) and has cytoplasmic functions (Schmid et al 2009;Millonigg et al 2014). Mammalian PAPD5 is localized in the cell nucleus with an enrichment in nucleoli (Lubas et al 2011;Rammelt et al 2011;Ogami et al 2013) in agreement with roles in oligoadenylation of RNA polymerase I transcripts (Shcherbik et al 2010) and snoRNA processing intermediates (Berndt et al 2012). However, functional data are also consistent with a cytoplasmic role (Burns et al 2011).…”

“…Identified substrates of TRAMP-dependent degradation or processing in yeast are so far restricted to nuclear RNAs. Similar mechanisms seem to operate in higher eukaryotes (West et al 2006;Shcherbik et al 2010;Lubas et al 2011;Berndt et al 2012). In mammalian cells, oligoadenylation of cytoplasmic mRNAs and rRNA fragments has been described.…”

PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

“…In human and murine liver cells, 3′ adenylation mediated by the nucleotidyl transferase PAPD4 has been shown to stabilize miR-122 (19). In contrast, PAPD5 was recently found to aid in the maturation of SNORA63 and other small nucleolar RNAs in a pathway where oligoadenylation by PAPD5 is followed by 3′-to-5′ trimming by the exonuclease PARN (38,39) (Fig. S6).…”

Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

“…31 It also functions as an exoribonuclease reminiscent to the function of PARN that has been recently found to be mutated in both DC and pulmonary fibrosis. 32 Both LIG4 and RTEL1 are involved in the maintenance of genomic stability, as they are both involved in pathways that repair double-strand breaks. LIG4 is an ATP-dependent DNA ligase that joins double-strand breaks during non-homologous end joining, and RTEL1 (a protein that is mutated in a subset of DC) is an ATPdependent DNA helicase, which has an important role in telomere-length regulation.…”