The Exoribonuclease Nibbler Controls 3′ End Processing of MicroRNAs in Drosophila

Liu, Nan; Abe, Masashi; Sabin, Leah R.; Hendriks, Gert‐Jan; Naqvi, Ammar S.; Yu, Zhenming; Cherry, Sara; Bonini, Nancy M.

doi:10.1016/j.cub.2011.10.006

Cited by 131 publications

(148 citation statements)

References 33 publications

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“…Our results show that 3′ adenylation of oncomiR miR-21 by the nucleotidyl transferase PAPD5 may similarly lead to its degradation by targeting it for 3′ end trimming by exoribonuclease PARN. This enzyme thus is a human ortholog of the exonuclease Nibbler, which was recently discovered to trim the 3′ ends of miRNAs in Drosophila (43,44). PARN was recently also shown to trim the 3′ arm of human pre-miR-451 in the 3′-to-5′ direction as the final step in the maturation pathway of this miRNA (50).…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, several posttranscriptional mechanisms have been uncovered that enable the fine-grained regulation of individual miRNAs beyond the canonical maturation pathway (3,43,44). Next-generation sequencing of miRNAs has revealed a wide variety of miRNA variants that may be produced by differential excision by DICER1 or nucleotide additions to the 3′ ends of miRNAs or their precursors (11,45).…”

Section: Discussionmentioning

confidence: 99%

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

Boele

Persson

Shin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

138

143

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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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Boele

Persson

Shin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

138

143

View full text Add to dashboard Cite

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“…Following acceptance of this work, the Bonini and Zamore labs reported that the 39-59 exoribonuclease Nibbler trims the 39 ends of Drosophila miRNAs (Han et al 2011;Liu et al 2011).…”

Section: Note Added In Proofmentioning

confidence: 99%

Common and distinct patterns of terminal modifications to mirtrons and canonical microRNAs

Westholm¹,

Ladewig²,

Okamura³

et al. 2011

RNA

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Nucleotide modifications to microRNAs or their precursors can influence their processing and/or activity. A challenge to their analysis is the lack of independent references for the termini generated by primary processing; typically, these are empirically assigned as the most abundant mapped reads. Mirtrons offer such an independent measure since these microRNA hairpins are defined by splicing. Consequently, mirtron-derived reads that deviate from splice sites reflect modification following primary processing. Analysis in Drosophila revealed multiple modification patterns, including select alterations of 59 termini, many 39 resection events, and unexpectedly abundant 39 untemplated monouridylation. Resections occur on mature AGO1-loaded species, whereas uridylation occurs on pre-miRNAs but is compatible with dicing and AGO1 loading. Strikingly, we found many mirtrons whose modified reads are more abundant than those produced by primary processing. In some cases, these abundant modified reads matched the genome owing to fortuitous uridines in downstream flanking exons, thus highlighting the value of an independent reference for the primary-processed sequence. We could further extend the principle of abundant and preferred uridylation of mirtrons, relative to canonical pre-miRNAs, to Caenorhabditis elegans, mouse, and human. Finally, we found that 39 resection occurs broadly across AGO1-loaded canonical miRNA and star species. Altogether, these findings substantially broaden the complexity of terminal modification pathways acting upon small regulatory RNAs.

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“…associated neurodegeneration in Drosophila revealed an intriguing pattern of miR-34 isoforms: Although multiplelength isoforms of miR-34 are generated, only the short isoform accumulates with age (Liu et al 2012). Furthermore, the generation of isoforms of miR-34 requires 39 end trimming by a novel 39-to-59 exonuclease, Nibbler (Nbr) (Han et al 2011;Liu et al 2011), highlighting the potential importance of regulation of miRNA length in age-associated processes.…”

mentioning

confidence: 99%

Impact of age-associated increase in 2′-O-methylation of miRNAs on aging and neurodegeneration in Drosophila

et al. 2014

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MicroRNAs (miRNAs) are 20-to~24-nucleotide (nt) small RNAs that impact a variety of biological processes, from development to age-associated events. To study the role of miRNAs in aging, studies have profiled the levels of miRNAs with time. However, evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Here, by examining the expression pattern of miRNAs by Northern blot analysis, we found that Drosophila miRNAs show distinct isoform pattern changes with age. Surprisingly, an increase of some miRNAs reflects increased 29-O-methylation of select isoforms. Small RNA deep sequencing revealed a global increase of miRNAs loaded into Ago2, but not into Ago1, with age. Our data suggest increased loading of miRNAs into Ago2, but not Ago1, with age, indicating a mechanism for differential loading of miRNAs with age between Ago1 and Ago2. Mutations in Hen1 and Ago2, which lack 29-O-methylation of miRNAs, result in accelerated neurodegeneration and shorter life span, suggesting a potential impact of the ageassociated increase of 29-O-methylation of small RNAs on age-associated processes. Our study highlights that miRNA 29-O-methylation at the 39 end is modulated by differential partitioning of miRNAs between Ago1 and Ago2 with age and that this process, along with other functions of Ago2, might impact age-associated events in Drosophila.

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The Exoribonuclease Nibbler Controls 3′ End Processing of MicroRNAs in Drosophila

Cited by 131 publications

References 33 publications

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

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

Common and distinct patterns of terminal modifications to mirtrons and canonical microRNAs

Impact of age-associated increase in 2′-O-methylation of miRNAs on aging and neurodegeneration in Drosophila

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