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

Abstract

Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3′ end, and moreover that the 3′ end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3′-to-5′ direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.nucleotidyl transferase | microRNA processing

Gld2-catalyzed 3′ monoadenylation of miRNAs in the hippocampus has no detectable effect on their stability or on animal behavior

“…In this regard, the hippocampus and primary human fibroblasts are roughly similar. However, these values vary substantially from those in human embryonic stem cells and several cancer cell lines in which ∼50% or more of miRNAs are monoadenylated (Burroughs et al 2010;Wyman et al 2011), among the most prevalent of which is miR21 (Boele et al 2014). In mouse liver, miR122, the most abundant miRNA in that tissue, is ∼75% monoadenylated (Katoh et al 2009).…”

“…It might be argued that because PARN is so important for miRNA destruction (Boele et al 2014;Katoh et al 2015), this enzyme might be absent from the hippocampus and thus nonadenylated miRNAs are stable. However, we have shown that PARN is quite abundant in that tissue, that it resides in a complex containing Gld2, and that these two enzymes colocalize in dendritic spines .…”

Non-coding RNAs: An emerging player in DNA damage response

“…Previous studies have shown that the binding of pre-miRNAs to protein components such as MCPIP1 can facilitate the process of pre-miRNA degradation [52]. A recent study reported that the nucleotidyl transferase PAP associated domain containing 5 (PAPD5) and the poly(A)-specific ribonuclease PARN can work together to mediate 3 0 adenylation and subsequent degradation of miR-21 [53]. However, the detailed mechanisms whereby DNA damage can induce miRNA degradation and turnover need to be further investigated.…”

Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease

“…PARN has been shown to deadenylate noncoding RNAs such as small nucleolar RNAs and microRNAs (miRNAs) that are adenylated by the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5; also known as TRF4-2) (18,19). PAPD5 acts within the TRAMP complex (TRF4-2, AIR2, MTR4) to add short oligo(A) extensions to nuclear RNAs, leading to their destruction by the exosome (17,20).…”