Identification of a novel human nuclear-encoded mitochondrial poly(A) polymerase

Tomecki, Rafał; Dmochowska, Aleksandra; Gewartowski, Kamil; Dziembowski, Andrzej; Stępień, Piotr P.

doi:10.1093/nar/gkh923

Cited by 149 publications

(196 citation statements)

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“…Instead, an encoded dodecamer sequence regulates RNA stability in this system (10). In human mitochondria, it appears that polyadenylation positively or negatively regulates steady-state levels of mitochondrial mRNAs in a transcript-specific manner (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a new class of PAPs was described in several eukaryotes. Members of this class include Cid1p and Cid13p in the fission yeast Schizosaccharomyces pombe (29,30), GLD-2 in Caenorhabditis elegans (31), and hmtPAP in human mitochondria (11,12). Members of this novel PAP family diverge from canonical PAPs, exhibiting relatively low homology within the catalytic domain.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, Wang et al have reported that in C. elegans, an RNA-binding protein termed GLD-3 binds to and stimulates the polyadenylation activity of GLD-2 (31). Another member of the novel PAP family, hmtPAP, has been shown to be the bona fide mitochondrial PAP in humans (11,12). Mitochondria from cells in which hmtPAP expression was downregulated by RNA interference (RNAi) showed decreased poly(A) tail lengths.…”

Section: Introductionmentioning

confidence: 99%

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Targeted depletion of a mitochondrial nucleotidyltransferase suggests the presence of multiple enzymes that polymerize mRNA 3′ tails in Trypanosoma brucei mitochondria

Kao

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2007

Molecular and Biochemical Parasitology

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Polyadenylation plays an important role in regulating RNA stability in Trypanosoma brucei mitochondria. To date, little is known about the enzymes responsible for the addition of mRNA 3′ tails in this system. In this study, we characterize a trypanosome homolog of the human mitochondrial poly(A) polymerase, which we term kPAP2. kPAP2 is mitochondrially localized and expressed in both bloodstream and procyclic form trypanosomes. Targeted gene depletion using RNAi showed that kPAP2 is not required for T. brucei growth in either bloodstream or procyclic life stages, nor is it essential for differentiation from bloodstream to procyclic form. We also demonstrate that steady state abundance of several mitochondrial RNAs was largely unaffected upon kPAP2 downregulation. Interestingly, mRNA 3′ tail analysis of several mRNAs from both life cycle stages in uninduced kPAP2 RNAi cells demonstrated that tail length and uridine content are both regulated in a transcript-specific manner. mRNA-specific tail lengths were maintained upon kPAP2 depletion. However, the percentage of uridine residues in 3′ tails was increased, and conversely the percentage of adenosine residues was decreased, in a distinct subset of mRNAs when kPAP2 levels were downregulated. Thus, kPAP2 apparently contributes to the incorporation of adenosine residues in 3′ tails of some, but not all, mitochondrial mRNAs. Together, these data suggest that multiple nucleotidyltransferases act on mitochondrial mRNA 3′ ends, and that these enzymes are somewhat redundant and subject to complex regulation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeted depletion of a mitochondrial nucleotidyltransferase suggests the presence of multiple enzymes that polymerize mRNA 3′ tails in Trypanosoma brucei mitochondria

Kao

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2007

Molecular and Biochemical Parasitology

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“…Kwak et al (20) recently described five human orthologs of the Cid1 protein, named Hs1 to Hs5. Among these, Hs4 is responsible for the synthesis of long poly(A) tails in human mitochondria (37).…”

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confidence: 99%

Requirement of Fission Yeast Cid14 in Polyadenylation of rRNAs

Win

Draper

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et al. 2006

Molecular and Cellular Biology

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Polyadenylation in eukaryotes is conventionally associated with increased nuclear export, translation, and stability of mRNAs. In contrast, recent studies suggest that the Trf4 and Trf5 proteins, members of a widespread family of noncanonical poly(A) polymerases, share an essential function in Saccharomyces cerevisiae that involves polyadenylation of nuclear RNAs as part of a pathway of exosome-mediated RNA turnover. Substrates for this pathway include aberrantly modified tRNAs and precursors of snoRNAs and rRNAs. Here we show that Cid14 is a Trf4/5 functional homolog in the distantly related fission yeast Schizosaccharomyces pombe. Unlike trf4 trf5 double mutants, cells lacking Cid14 are viable, though they suffer an increased frequency of chromosome missegregation. The Cid14 protein is constitutively nucleolar and is required for normal nucleolar structure. A minor population of polyadenylated rRNAs was identified. These RNAs accumulated in an exosome mutant, and their presence was largely dependent on Cid14, in line with a role for Cid14 in rRNA degradation. Surprisingly, both fully processed 25S rRNA and rRNA processing intermediates appear to be channeled into this pathway. Our data suggest that additional substrates may include the mRNAs of genes involved in meiotic regulation. Polyadenylation-assisted nuclear RNA turnover is therefore likely to be a common eukaryotic mechanism affecting diverse biological processes.In eukaryotic cells, most genes are transcribed into precursor messenger RNAs that have to undergo several processing events before maturation, including addition of a cap structure to the 5Ј terminus, removal of introns by splicing, and 3Ј cleavage and polyadenylation. A key player in the polyadenylation process is the nuclear poly(A) polymerase (PAP

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“…RNA was run on a 0.8% agarose-formaldehyde gel and blotted onto nylon membrane as described previously (Tomecki et al, 2004). Amount of mitochondrial protein (quantified by the Bradford assay) in the starting preparation was used to normalize the amount of RNA in each lane.…”

Section: Rna Preparation and Northern Hybridizationmentioning

confidence: 99%

Balance between Transcription and RNA Degradation Is Vital forSaccharomyces cerevisiaeMitochondria: Reduced Transcription Rescues the Phenotype of Deficient RNA Degradation

Rogowska

Puchta

Czarnecka

et al. 2006

MBoC

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The Saccharomyces cerevisiae SUV3 gene encodes the helicase component of the mitochondrial degradosome (mtEXO), the principal 3 -to-5 exoribonuclease of yeast mitochondria responsible for RNA turnover and surveillance. Inactivation of SUV3 (suv3⌬) causes multiple defects related to overaccumulation of aberrant transcripts and precursors, leading to a disruption of mitochondrial gene expression and loss of respiratory function. We isolated spontaneous suppressors that partially restore mitochondrial function in suv3⌬ strains devoid of mitochondrial introns and found that they correspond to partial loss-of-function mutations in genes encoding the two subunits of the mitochondrial RNA polymerase (Rpo41p and Mtf1p) that severely reduce the transcription rate in mitochondria. These results show that reducing the transcription rate rescues defects in RNA turnover and demonstrates directly the vital importance of maintaining the balance between RNA synthesis and degradation. INTRODUCTIONThe degradation of RNA is an essential element in the expression of genetic information. It is required to control RNA abundance and thus gene expression and to eliminate aberrant or defective molecules that inevitably form during RNA synthesis and maturation (RNA surveillance) (Vasudevan and Peltz, 2003). The posttranscriptional mechanisms affecting mitochondrial gene expression, including RNA turnover, are of particular importance because transcriptional control is relatively simple and rudimentary. The single RNA polymerase (RNAP) of Saccharomyces cerevisiae mitochondria is composed of only two nuclear-encoded protein subunits-the core enzyme encoded by the RPO41 gene and a transcription initiation factor encoded by the MTF1 gene (Masters et al., 1987;Jang and Jaehning, 1991). The RNAP holoenzyme recognizes a simple nonanucleotide promoter sequence (Osinga et al., 1982;Mangus et al., 1994) and initiates synthesis of at least 13 primary multicistronic transcripts that undergo extensive processing to form mature RNAs (Christianson and Rabinowitz, 1983;Tzagoloff and Myers, 1986;Foury et al., 1998;Gagliardi et al., 2004;Schafer, 2005). Such organization leaves little room for regulation at the transcription initiation level and makes posttranscriptional processes, including RNA degradation, key control points for mitochondrial gene expression.The enzymes controlling RNA turnover in cells and organelles show great evolutionary divergence and are only partially conserved between mitochondria of different organisms (Gagliardi et al., 2004). The enzymatic activity responsible for turnover is, however, on the basic level, similar in all the systems discovered so far-it is that of a 3Ј-to-5Ј processive exoribonuclease, either hydrolytic or phosphorolytic. In most cases, the exoribonuclease activity is contained in a larger multiprotein complex that, in addition to exoribonucleases, also contains RNA helicases, and in certain cases, endonucleases. A model example of such a complex is the eubacterial degradosome (Carpousis, 2002).The first mitoc...

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Identification of a novel human nuclear-encoded mitochondrial poly(A) polymerase

Cited by 149 publications

References 88 publications

Targeted depletion of a mitochondrial nucleotidyltransferase suggests the presence of multiple enzymes that polymerize mRNA 3′ tails in Trypanosoma brucei mitochondria

Targeted depletion of a mitochondrial nucleotidyltransferase suggests the presence of multiple enzymes that polymerize mRNA 3′ tails in Trypanosoma brucei mitochondria

Requirement of Fission Yeast Cid14 in Polyadenylation of rRNAs

Balance between Transcription and RNA Degradation Is Vital forSaccharomyces cerevisiaeMitochondria: Reduced Transcription Rescues the Phenotype of Deficient RNA Degradation

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