Terminal modification, sequence, length, and PIWI-protein identity determine piRNA stability

Ildar Gainetdinov, Cansu Colpan, Katharine Cecchini, Amena Arif, Karina Jouravleva, Paul Albosta, Joel Vega-Badillo, Yongjin Lee, Deniz M. Özata, Phillip D. Zamore

Research output: Contribution to journalArticlepeer-review


In animals, PIWI-interacting RNAs (piRNAs) silence transposons, fight viral infections, and regulate gene expression. piRNA biogenesis concludes with 3′ terminal trimming and 2′-O-methylation. Both trimming and methylation influence piRNA stability. Our biochemical data show that multiple mechanisms destabilize unmethylated mouse piRNAs, depending on whether the piRNA 5′ or 3′ sequence is complementary to a trigger RNA. Unlike target-directed degradation of microRNAs, complementarity-dependent destabilization of piRNAs in mice and flies is blocked by 3′ terminal 2′-O-methylation and does not require base pairing to both the piRNA seed and the 3′ sequence. In flies, 2′-O-methylation also protects small interfering RNAs (siRNAs) from complementarity-dependent destruction. By contrast, pre-piRNA trimming protects mouse piRNAs from a degradation pathway unaffected by trigger complementarity. In testis lysate and in vivo, internal or 3′ terminal uridine- or guanine-rich tracts accelerate pre-piRNA decay. Loss of both trimming and 2′-O-methylation causes the mouse piRNA pathway to collapse, demonstrating that these modifications collaborate to stabilize piRNAs.

Original languageEnglish (US)
Pages (from-to)4826-4842.e8
JournalMolecular Cell
Issue number23
StatePublished - Dec 2 2021


  • 2'-O-methylation
  • PIWI
  • RNA stability
  • RNA turnover
  • piRNA
  • piwi-interacting RNA
  • siRNA
  • small RNA
  • small interfering RNA
  • target-directed microRNA degradation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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