Function and Regulation of Human Terminal Uridylyltransferases

Abstract

RNA uridylylation plays a pivotal role in the biogenesis and metabolism of functional RNAs, and regulates cellular gene expression. RNA uridylylation is catalyzed by a subset of proteins from the non-canonical terminal nucleotidyltransferase family. In human, three proteins (TUT1, TUT4, and TUT7) have been shown to exhibit template-independent uridylylation activity at 3′-end of specific RNAs. TUT1 catalyzes oligo-uridylylation of U6 small nuclear (sn) RNA, which catalyzes mRNA splicing. Oligo-uridylylation of U6 snRNA is required for U6 snRNA maturation, U4/U6-di-snRNP formation, and U6 snRNA recycling during mRNA splicing. TUT4 and TUT7 catalyze mono- or oligo-uridylylation of precursor let-7 (pre–let-7). Let-7 RNA is broadly expressed in somatic cells and regulates cellular proliferation and differentiation. Mono-uridylylation of pre–let-7 by TUT4/7 promotes subsequent Dicer processing to up-regulate let-7 biogenesis. Oligo-uridylylation of pre–let-7 by TUT4/7 is dependent on an RNA-binding protein, Lin28. Oligo-uridylylated pre–let-7 is less responsive to processing by Dicer and degraded by an exonuclease DIS3L2. As a result, let-7 expression is repressed. Uridylylation of pre–let-7 depends on the context of the 3′-region of pre–let-7 and cell type. In this review, we focus on the 3′ uridylylation of U6 snRNA and pre-let-7, and describe the current understanding of mechanism of activity and regulation of human TUT1 and TUT4/7, based on their crystal structures that have been recently solved.

Repeated Evolution of Inactive Pseudonucleases in a Fungal Branch of the Dis3/RNase II Family of Nucleases

“…Lastly, we note that the canonical nuclease function of Dis3L2 enzymes requires their canonical substrates: RNAs that have poly(U) tails added by terminal U-transferases such as S. pombe cid1 and cid16, and human TUT1, TUT4, and TUT7 ( Yashiro and Tomita 2018 ). In the absence of terminal U-transferase activity, there would be few poly(U)-tailed substrates, removing selective pressure to retain Dis3L2’s terminal U-targeted nuclease activity.…”

UPF1-Mediated RNA Decay—Danse Macabre in a Cloud

“…Both HMD targets and some ribosome-bound NMD decay intermediates are oligouridylated by TUTases as a necessary step of their regulated degradation [ 101 , 102 , 189 ]. Oligouridylation is generally important for the regulated turnover of many RNAs, including miRNAs and mRNAs (reviewed in [ 218 , 219 , 220 , 221 ]).…”

Structure and mechanism of CutA, RNA nucleotidyl transferase with an unusual preference for cytosine

“…A growing number of so-called poly(U) polymerases (PUPs), also termed terminal uridyl transferases (TUTases), which mostly add uridyl ribonucleotides to the 3′-end of RNA, have recently been described. These are involved in multiple pathways of RNA regulation but usually induce the accelerated decay of target RNA molecules ( 6 , 7 ) through a mechanism in which uridine tagging at the 3′-end of a transcript by a TUTase is followed by decapping and 5′-3′ or 3′-5′ exonucleolytic degradation ( 8–10 ). In addition to 3′ uridine tagging, 3′ guanylation and cytidylation in different species have also been reported ( 11–13 ).…”

“…Humans have three uridyl transferases (TENT1/TUT1, TENT3A/ZCCHC11/TUT4 and TENT3B/TUT7/ZCCHC6) and in S. pombe , the main non-canonical uridyl transferase is Cid1 ( 6 , 7 ). Cid1 can add both uridines and adenosines in vitro but is specific for U in vivo ( 18–21 ).…”