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PIWI-interacting RNAs: small RNAs with big functions

Abstract

In animals, PIWI-interacting RNAs (piRNAs) of 21–35 nucleotides in length silence transposable elements, regulate gene expression and fight viral infection. piRNAs guide PIWI proteins to cleave target RNA, promote heterochromatin assembly and methylate DNA. The architecture of the piRNA pathway allows it both to provide adaptive, sequence-based immunity to rapidly evolving viruses and transposons and to regulate conserved host genes. piRNAs silence transposons in the germ line of most animals, whereas somatic piRNA functions have been lost, gained and lost again across evolution. Moreover, most piRNA pathway proteins are deeply conserved, but different animals employ remarkably divergent strategies to produce piRNA precursor transcripts. Here, we discuss how a common piRNA pathway allows animals to recognize diverse targets, ranging from selfish genetic elements to genes essential for gametogenesis.

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Fig. 1: Genomic sources of piRNAs.
Fig. 2: Type I piRNA biogenesis in Caenorhabditis elegans.
Fig. 3: piRNA biogenesis in most animals.
Fig. 4: The preference of PIWI proteins for t1A targets is one of the sources of the g1U bias of piRNAs.
Fig. 5: Diverse functions of piRNAs.

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Acknowledgements

The authors thank J. Brennecke, W. Tang and members of the Zamore laboratory for discussions and critical comments on the manuscript.

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Nature Reviews Genetics thanks A. Kalmykova, R. Ketting and H. Siomi for their contribution to the peer review of this work.

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D.M.O., I.G. and A.Z. researched content for the article. All authors contributed to discussing the content, writing the manuscript, and reviewing or editing the manuscript before submission.

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Correspondence to Phillip D. Zamore.

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Glossary

Spermatogonial

Related to spermatogonia, which are the undifferentiated germ cells located at the periphery of seminiferous tubules. They undergo mitosis and later give rise to developing spermatocytes.

Heterochromatic

Consisting of heterochromatin, the tightly packed form of DNA whose histones are heavily modified with repressive marks, typically histone H3 lysine 9 trimethylation (H3K9me3).

Canonical transcription

This standard transcription requires a promoter (typically marked by histone H3 lysine 4 trimethylation (H3K4me3)) and generates RNA with a 5ʹ 7-methylguanosine cap and a 3ʹ poly(A) tail.

Pachytene

The stage of meiotic prophase I when homologous recombination occurs.

Initiator piRNA

A PIWI-interacting RNA (piRNA) that guides a PIWI protein to slice a piRNA precursor transcript, triggering production of responder and trailing piRNAs from it.

Pre-pre-piRNA

A 5ʹ monophosphorylated long RNA created by an initiator PIWI-interacting RNA (piRNA)-guided PIWI-catalysed slicing of a piRNA precursor transcript.

Responder piRNA

A PIWI-interacting RNA (piRNA) whose 5ʹ end is generated by initiator piRNA-guided PIWI-catalysed slicing of a piRNA precursor transcript.

Pre-piRNA

The intermediate product of PIWI-interacting RNA (piRNA) biogenesis loaded into a PIWI protein. Pre-piRNAs are 3ʹ-to-5ʹ trimmed and 2ʹ-O-methylated at their 3ʹ termini to yield mature piRNAs.

Trailing pre-piRNAs

A string of tail-to-head, phased trailing pre-piRNAs follows a responder piRNA. Both 5ʹ and 3ʹ ends of trailing piRNAs are made by the stepwise endonucleolytic fragmentation of a piRNA precursor transcript.

k cat

In Michaelis–Menten enzyme kinetics, the catalytic constant kcat represents the maximum number of substrate molecules converted to product per active site per unit time.

PIWI slicer activity

Endonucleolytic cleavage of the target RNA catalysed by PIWI-interacting RNA (piRNA)-guided PIWI proteins.

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Ozata, D.M., Gainetdinov, I., Zoch, A. et al. PIWI-interacting RNAs: small RNAs with big functions. Nat Rev Genet 20, 89–108 (2019). https://doi.org/10.1038/s41576-018-0073-3

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