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BBA - Gene Regulatory Mechanisms (v.1779, #4)

Editorial Board (pp. ii).

Special issue: Novel RNA nucleotidyl transferases and gene regulation by Chris J. Norbury (pp. 205-205).

Determinants of substrate specificity in RNA-dependent nucleotidyl transferases by Georges Martin; Sylvie Doublié; Walter Keller (pp. 206-216).

Poly(A) polymerases were identified almost 50 years ago as enzymes that add multiple AMP residues to the 3′ ends of primer RNAs without use of a template from ATP as cosubstrate and with release of pyrophosphate. Based on sequence homology of a signature motif in the catalytic domain, poly(A) polymerases were later found to belong to a superfamily of nucleotidyl transferases acting on a very diverse array of substrates. Enzymes belonging to the superfamily can add from single nucleotides of AMP, CMP or UMP to RNA, antibiotics and proteins but also homopolymers of many hundred residues to the 3′ ends of RNA molecules.The recently reported structures of several nucleotidyl transferases facilitate the study of the catalytic mechanisms of these very diverse enzymes. Numerous structures of CCA-adding enzymes have now revealed all steps in the formation of a CCA tail at the 3′ end of tRNAs. In addition, structures of poly(A) polymerases and uridylyl transferases are now available as binary and ternary complexes with incoming nucleotide and RNA primer. Some of these proteins undergo significant conformational changes after substrate binding. This is proposed to be an indication for an induced fit mechanism that drives substrate selection and leads to catalysis. Insights from recent structures of ternary complexes indicate an important role for the primer molecule in selecting the incoming nucleotide.

Keywords: Nucleotidyl transferase; Terminal uridylyl transferase; CCA-adding enzyme; Poly(A) polymerase; Catalytic mechanism

Translational control by cytoplasmic polyadenylation in Xenopus oocytes by Helois E. Radford; Hedda A. Meijer; Cornelia H. de Moor (pp. 217-229).

Elongation of the poly(A) tails of specific mRNAs in the cytoplasm is a crucial regulatory step in oogenesis and early development of many animal species. The best studied example is the regulation of translation by cytoplasmic polyadenylation elements (CPEs) in the 3′ untranslated region of mRNAs involved in Xenopus oocyte maturation. In this review we discuss the mechanism of translational control by the CPE binding protein (CPEB) in Xenopus oocytes as follows:1.The cytoplasmic polyadenylation machinery such as CPEB, the subunits of cleavage and polyadenylation specificity factor (CPSF), symplekin, Gld-2 and poly(A) polymerase (PAP).2.The signal transduction that leads to the activation of CPE-mediated polyadenylation during oocyte maturation, including the potential roles of kinases such as MAPK, Aurora A, CamKII, cdk1/Ringo and cdk1/cyclin B.3.The role of deadenylation and translational repression, including the potential involvement of PARN, CCR4/NOT, maskin, pumilio, Xp54 (Ddx6, Rck), other P-body components and isoforms of the cap binding initiation factor eIF4E.Finally we discuss some of the remaining questions regarding the mechanisms of translational regulation by cytoplasmic polyadenylation and give our view on where our knowledge is likely to be expanded in the near future.

Keywords: Cytoplasmic polyadenylation; Oocyte; Meiotic maturation; Translational control; Deadenylation

Non-canonical poly(A) polymerase in mammalian gametogenesis by Shin-ichi Kashiwabara; Tomoko Nakanishi; Masanori Kimura; Tadashi Baba (pp. 230-238).

Polyadenylation of mRNA precursors initially occurs in the nucleus of eukaryotic cells, and the polyadenylated mRNAs are then transported into the cytoplasm. Because the length of the poly(A) tail is implicated in various aspects of mRNA metabolism, including the transport into the cytoplasm, stability, and translational control, processing of mRNA precursors at the 3′-end is important for post-transcriptional gene regulation. In particular, the lengthening, maintenance, and shortening of poly(A) tails in the cytoplasm are all essential for modulation of gametogenesis. Here we focus on the functional roles of mouse Tpap and Gld-2 in spermatogenesis and oocyte maturation, respectively.

Keywords: Poly(A) polymerase; TPAP; Spermatogenesis; GLD-2; Oocyte maturation; Cytoplasmic polyadenylation; Mouse

The nuclear RNA surveillance machinery: The link between ncRNAs and genome structure in budding yeast? by Jonathan Houseley; David Tollervey (pp. 239-246).

The TRAMP polyadenylation complexes have well-established functions in RNA surveillance, stimulating degradation by the 3′ to 5′ exonuclease activity of the exosome on a wide range of nuclear RNAs and RNA–protein complexes. Known targets include some of the non-protein coding RNA transcripts (ncRNAs), which are apparently widely transcribed from yeast and mammalian genomes. We will discuss potential mechanisms of TRAMP recruitment and exosome activation during RNA surveillance and degradation. Less well-understood observations link both the TRAMP and exosome complexes to chromatin structure and DNA repair, and we will speculate on the potential significance of these activities.

Keywords: Poly(A) polymerase; TRAMP; ncRNA; Chromatin; RNA surveillance

Polynucleotide phosphorylase and the archaeal exosome as poly(A)-polymerases by Shimyn Slomovic; Victoria Portnoy; Shlomit Yehudai-Resheff; Ela Bronshtein; Gadi Schuster (pp. 247-255).

The addition of poly(A)-tails to RNA is a phenomenon common to almost all organisms. Not only homopolymeric poly(A)-tails, comprised exclusively of adenosines, but also heteropolymeric poly(A)-rich extensions, which include the other three nucleotides as well, have been observed in bacteria, archaea, chloroplasts, and human cells. Polynucleotide phosphorylase (PNPase) and the archaeal exosome, which bear strong similarities to one another, both functionally and structurally, were found to polymerize the heteropolymeric tails in bacteria, spinach chloroplasts, and archaea. As phosphorylases, these enzymes use diphosphate nucleotides as substrates and can reversibly polymerize or degrade RNA, depending on the relative concentrations of nucleotides and inorganic phosphate. A possible scenario, illustrating the evolution of RNA polyadenylation and its related functions, is presented, in which PNPase (or the archaeal exosome) was the first polyadenylating enzyme to evolve and the heteropolymeric tails that it produced, functioned in a polyadenylation-stimulated RNA degradation pathway. Only at a later stage in evolution, did the poly(A)-polymerases that use only ATP as a substrate, hence producing homopolymeric adenosine extensions, arise. Following the appearance of homopolymeric tails, a new role for polyadenylation evolved; RNA stability. This was accomplished by utilizing stable poly(A)-tails associated with the mature 3′ ends of transcripts. Today, stable polyadenylation coexists with unstable heteropolymeric and homopolymeric tails. Therefore, the heteropolymeric poly(A)-rich tails, observed in bacteria, organelles, archaea, and human cells, represent an ancestral stage in the evolution of polyadenylation.

Keywords: RNA polyadenylation; RNA degradation; PNPase; Exosome; Heteropolymeric tails

RNA recognition by 3′-to-5′ exonucleases: The substrate perspective by Hend Ibrahim; Jeffrey Wilusz; Carol J. Wilusz (pp. 256-265).

The 3′-to-5′ exonucleolytic decay and processing of a variety of RNAs is an essential feature of RNA metabolism in all cells. The 3′–5′ exonucleases, and in particular the exosome, are involved in a large number of pathways from 3′ processing of rRNA, snRNA and snoRNA, to decay of mRNAs and mRNA surveillance. The potent enzymes performing these reactions are regulated to prevent processing of inappropriate substrates whilst mature RNA molecules exhibit several attributes that enable them to evade 3′–5′ attack. How does an enzyme perform such selective activities on different substrates? The goal of this review is to provide an overview and perspective of available data on the underlying principles for the recognition of RNA substrates by 3′-to-5′ exonucleases.

Keywords: Exonuclease; 3′-to-5′ exonuclease; Exosome; RNA decay; RNA stability; RNA processing

Polyadenylation in mammalian mitochondria: Insights from recent studies by Takashi Nagaike; Tsutomu Suzuki; Takuya Ueda (pp. 266-269).

Polyadenylation in animal mitochondria is very unique. Unlike other systems, polyadenylation is needed to generate UAA stop codons that are not encoded in mitochondrial (mt) DNA. In some cases, polyadenylation is required for the mt tRNA maturation by editing of its 3′ termini. Furthermore, recent studies on human mt poly(A) polymerase (PAP) and PNPase provide new insights and questions for the regulatory mechanism and functional role of polyadenylation in human mitochondria.

Keywords: Mitochondrial; Polyadenylation; Poly(A) polymerase; mRNA stability

Terminal RNA uridylyltransferases of trypanosomes by Ruslan Aphasizhev; Inna Aphasizheva (pp. 270-280).

Terminal RNA uridylyltransferases (TUTases) are functionally and structurally diverse nucleotidyl transferases that catalyze template-independent 3′ uridylylation of RNAs. Within the DNA polymerase β-type superfamily, TUTases are closely related to non-canonical poly(A) polymerases. Studies of U-insertion/deletion RNA editing in mitochondria of trypanosomatids identified the first TUTase proteins and their cellular functions: post-transcriptional uridylylation of guide RNAs by RNA editing TUTase 1 (RET1) and U-insertion mRNA editing by RNA editing TUTase 2 (RET2). The editing TUTases possess conserved catalytic and nucleotide base recognition domains, yet differ in quaternary structure, substrate specificity and processivity. The cytosolic TUTases TUT3 and TUT4 have also been identified in trypanosomes but their biological roles remain to be established. Structural analyses have revealed a mechanism of cognate nucleoside triphosphate selection by TUTases, which includes protein–UTP contacts as well as contribution of the RNA substrate. This review focuses on biological functions and structures of trypanosomal TUTases.

Keywords: RNA; RNA editing; Tutase; Poly (A) polymerase; Nucleotide transferase; Mitochondria; Trypanosoma; Leishmania

Specific and non-specific mammalian RNA terminal uridylyl transferases by Elena Guschina; Bernd-Joachim Benecke (pp. 281-285).

Uridylylation of various types of RNA molecules is a wide-spread phenomenon in molecular biology and is catalyzed by enzymes mediating the transfer of UMP residues to the 3′-ends of preexisting RNA. In most cases, however, the biological significance of these modifications remains elusive. As an exception, the RNA terminal uridylyl transferases (TUTases) of the mRNA editing complex within mitochondria of Trypanosomatidae have been characterized in great detail. Current knowledge on those editing enzymes has been summarized recently by R. Aphasizhev [Cell. Mol. Life Sci. 62 (2005) 2194–203] and, therefore, will not be included here. Rather, this review will focus on cellular non-editing TUTases, characterized by distinct modes of catalytic activity and substrate specificity. Putative biological functions of this rapidly growing number of RNA modifying enzymes are discussed.

Keywords: Uridylyl transferase; TUTase; RNA 3′-end modification; U6 snRNA; Poly(U) polymerase; Non-canonical poly(A) polymerase

The Cid1 poly(U) polymerase by Olivia S. Rissland; Chris J. Norbury (pp. 286-294).

The Schizosaccharomyces pombe cytoplasmic protein Cid1 acts as a poly(U) polymerase (PUP). Polyadenylated actin mRNA, a target of this activity, is uridylated upon arrest in S phase and is likely to be one of many such Cid1 targets. This RNA uridylation pathway appears to be conserved, as Cid1 orthologs in Arabidopsis thaliana, Caenorhabditis elegans and humans display PUP activity either in vitro or in Xenopus laevis oocytes. Here, we review the literature on Cid1, other PUPs and uridylation, a conserved and previously under-appreciated mechanism of RNA regulation.

Keywords: Poly(A) polymerase; Poly(U) polymerase; Cid1; RNA regulation; TUTase

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BBA - Gene Regulatory Mechanisms (v.1779, #4)