Structural highlights
Disease
DI3L2_HUMAN Nephroblastoma;Perlman syndrome. The disease is caused by variants affecting the gene represented in this entry.
Function
DI3L2_HUMAN 3'-5'-exoribonuclease that specifically recognizes RNAs polyuridylated at their 3' end and mediates their degradation. Component of an exosome-independent RNA degradation pathway that mediates degradation of both mRNAs and miRNAs that have been polyuridylated by a terminal uridylyltransferase, such as ZCCHC11/TUT4. Mediates degradation of cytoplasmic mRNAs that have been deadenylated and subsequently uridylated at their 3'. Mediates degradation of uridylated pre-let-7 miRNAs, contributing to the maintenance of embryonic stem (ES) cells. Essential for correct mitosis, and negatively regulates cell proliferation.[HAMAP-Rule:MF_03045][1] [2]
Publication Abstract from PubMed
RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3'-5' exoribonuclease that plays a critical role in human development. Dis3L2 independently degrades structured substrates, including coding and noncoding 3' uridylated RNAs. While the basis for Dis3L2's substrate recognition has been well characterized, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining cryogenic electron microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for RNA processing. We discovered a dramatic conformational change that is triggered by double-stranded RNA (dsRNA), repositioning two cold shock domains by 70 A. This movement exposes a trihelix linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not single-stranded RNA, degradation. These findings reveal the conformational plasticity of Dis3L2 and detail a mechanism of structured RNA degradation.
A shape-shifting nuclease unravels structured RNA.,Meze K, Axhemi A, Thomas DR, Doymaz A, Joshua-Tor L Nat Struct Mol Biol. 2023 Mar;30(3):339-347. doi: 10.1038/s41594-023-00923-x. , Epub 2023 Feb 23. PMID:36823385[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lubas M, Damgaard CK, Tomecki R, Cysewski D, Jensen TH, Dziembowski A. Exonuclease hDIS3L2 specifies an exosome-independent 3'-5' degradation pathway of human cytoplasmic mRNA. EMBO J. 2013 Jul 3;32(13):1855-68. PMID:23756462 doi:10.1038/emboj.2013.135
- ↑ Ustianenko D, Hrossova D, Potesil D, Chalupnikova K, Hrazdilova K, Pachernik J, Cetkovska K, Uldrijan S, Zdrahal Z, Vanacova S. Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNAs. RNA. 2013 Dec;19(12):1632-8. PMID:24141620 doi:10.1261/rna.040055.113
- ↑ Meze K, Axhemi A, Thomas DR, Doymaz A, Joshua-Tor L. A shape-shifting nuclease unravels structured RNA. Nat Struct Mol Biol. 2023 Mar;30(3):339-347. PMID:36823385 doi:10.1038/s41594-023-00923-x
