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Roles of a Trypanosoma Brucei 59/39 Exoribonuclease Homolog in Mrna Degradation

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Roles of a Trypanosoma Brucei 59/39 Exoribonuclease Homolog in Mrna Degradation JOBNAME: RNA 12#12 PAGE: 1 OUTPUT: Friday October 27 16:36:06 2006 csh/RNA/125784/rna2915 Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Roles of a Trypanosoma brucei 59/39 exoribonuclease homolog in mRNA degradation CHI-HO LI, HENRIETTE IRMER,1 DRIFA GUDJONSDOTTIR-PLANCK, SIMONE FREESE,2 HEIKE SALM, SIMON HAILE,3 ANTONIO M. ESTE´VEZ,4 and CHRISTINE CLAYTON Zentrum fu¨r Molekulare Biologie der Universita¨t Heidelberg (ZMBH), D-69120 Heidelberg, Germany ABSTRACT The genome of the kinetoplastid parasite Trypanosoma brucei encodes four homologs of the Saccharomyces cerevisiae 59/39 exoribonucleases Xrn1p and Xrn2p/Rat1p, XRNA, XRNB, XRNC, and XRND. In S. cerevisiae, Xrn1p is a cytosolic enzyme involved in degradation of mRNA, whereas Xrn2p is involved in RNA processing in the nucleus. Trypanosome XRND was found in the nucleus, XRNB and XRNC were found in the cytoplasm, and XRNA appeared to be in both compartments. XRND and XRNA were essential for parasite growth. Depletion of XRNA increased the abundances of highly unstable developmentally regulated mRNAs, perhaps by delaying a deadenylation-independent decay pathway. Degradation of more stable or unregulated mRNAs was not affected by XRNA depletion although a slight decrease in average poly(A) tail length was observed. We conclude that in trypanosomes 59/39 exonuclease activity is important in degradation of highly unstable, regulated mRNAs, but that for other mRNAs another step is more important in determining the decay rate. Keywords: Rat1; Trypanosoma; XRN1; degradation; mRNA INTRODUCTION whereas Rat1p/Xrn2p is located in the nucleus (Johnson 1997). Correspondingly, Xrn1p is more important in The processing of RNAs in mammalian cells involves mRNA degradation, whereas Rat1p is implicated primarily various endonucleases and exonucleases that affect site- in nuclear processing events. specific internal cleavages and trim the RNAs to their The major pathway of mRNA degradation in yeast mature lengths. Accurate regulation of gene expression also involves initial shortening of the poly(A) tail, followed by requires that mRNA and other RNAs be degraded in removal of the cap structure and degradation by Xrn1p a controlled fashion (Arraiano and Maquat 2003). In the (Decker and Parker 1994; Muhlrad et al. 1995; for reviews, yeast Saccharomyces cerevisiae, two major 59–39 exonu- see Decker and Parker 1994; Caponigro and Parker 1996; cleases, Xrn1/Sep1/Kem1 and Xrn2/Rat1, have been impli- Parker and Song 2004). S. cerevisiae and Schizosaccharo- cated in the 59 processing of RNAs. The two proteins have myces pombe that lack Xrn1p are viable although they show homologous N-terminal exonuclease domains (Bashkirov impaired growth (Larimer and Stevens 1990; Szankasi and et al. 1995) but differ in their location: Xrn1p is pre- Smith 1996). The S. cerevisiae mutant accumulates dead- dominantly (at least 90%) cytoplasmic (Heyer et al. 1995) enylated mRNAs (Hsu and Stevens 1993), which are gradually degraded by the exosome 39/59 exonuclease complex; Xrn1p mutations are synthetically lethal with Present address: 1Bernhard-Nocht-Institut fu¨r Tropenmedizin, Abtei- mutations in exosome activity (Johnson and Kolodner lung Molekularbiologie, Bernhard-Nocht-Str. 74, Hamburg, Germany. 1995; Anderson and Parker 1998). 2Max-Planck Institut for Medical Research, Heidelberg, Germany. 3Centre de recherche en Infectiologie, CHUQ, Pavillon Chul, 2705 Boul. Apart from the roles of S. cerevisiae Xrn1p in mRNA Laurier, Ste-Foy, Que G1V 4G2, Canada. degradation, there is evidence that it can promote micro- 4 Instituto de Parasitologia y Biomedicina ‘‘Lopez-Neyra’’, CSIC, Avda. tubule assembly in vitro, and xrn1 mutants are hypersen- del Conocimiento, s/n 18100 Armilla, Granada, Spain. Reprint requests to: Christine Clayton, Zentrum fu¨r Molekulare sitive to benomyl and defective in karyogamy (Johnson Biologie der Universita¨t Heidelberg (ZMBH), Im Neuenheimer Feld 282, 1997; Page et al. 1998; Solinger et al. 1999). Xrn1p has also D-69120 Heidelberg, Germany; e-mail: [email protected]; been shown to have DNA strand-exchange and exonucleo- fax: 49-6221-54-5894. Article published online ahead of print. Article and publication date are lytic activity (Kolodner et al. 1987; Dykstra et al. 1990; at http://www.rnajournal.org/cgi/doi/10.1261/rna.291506. Tishkoff et al. 1991; Liu and Gilbert 1994). The significance RNA (2006), 12:1–16. Published by Cold Spring Harbor Laboratory Press. Copyright Ó 2006 RNA Society. 1 rna2915 Li et al. ARTICLE RA JOBNAME: RNA 12#12 PAGE: 2 OUTPUT: Friday October 27 16:36:07 2006 csh/RNA/125784/rna2915 Downloaded from rnajournal.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Li et al. of these other activities is subject to debate since it is not In mammals, a subclass of highly unstable mRNAs clear how many of the effects are secondary to RNA containing AU-rich elements (AREs) has received particu- degradation defects. lar attention because of their roles in the control of cell The S. cerevisiae nuclear exonuclease Rat1p is, unlike proliferation and inflammation (Bevilacqua et al. 2003). Xrn1p, essential (Kenna et al. 1993). Its exonuclease activity Until very recently it was thought that the principal is similar to that of Xrn1p, but Rat1p/Xrn2p is present at pathway of degradation of mRNAs containing AREs was only one-tenth of the abundance of Xrn1p (Poole and deadenylation followed by 39/59 degradation by the Stevens 1995). Rat1 mutants show defects in the 59 exosome (Chen et al. 2001; Mukherjee et al. 2002). This processing of 5.8s rRNA (Amberg et al. 1992; Fang et al. conclusion was based mainly on results obtained in experi- 2005) and of snoRNAs (Lee et al. 2003), and in degrada- ments with in vitro extracts. Recently, however, siRNA tion of pre-mRNAs (Bousquet-Antonelli et al. 2000). The experiments targeting Xrn1 in human cells revealed a clear N-terminal 765 amino acids of Rat1p correspond to role for Xrn1 in degradation of an ARE-containing reporter residues 1–671 of Xrn1p; the most important difference RNA (Stoecklin et al. 2005). within this region is the insertion of a bipartite nuclear The Kinetoplastid protists include several parasites of localization signal in Rat1p. Since overexpressed Rat1p high economic and medical importance, infecting over (Poole and Stevens 1995) or expression of a mutant Rat1p 20 million people and reducing livestock production in lacking the nuclear localization signal (Johnson 1997) can tropical countries. Trypanosoma brucei and related (sali- complement the Dxrn1 mutant, and Xrn1p targeted to the varian) trypanosomes cause human sleeping sickness and nucleus can complement the conditional rat1-1 mutant of infect cattle throughout sub-Saharan Africa, and are trans- Rat1p (Johnson 1997), it appears that the major functional mitted by Tsetse flies; Trypanosoma cruzi is transmitted by difference between the two proteins is confined to their reduviid bugs in South and Middle America and is the localization. The functions of the long divergent C termini causative agent of Chagas disease; and the various Leish- (763 residues of Xrn1p and 241 residues of Rat1p) are as yet manias, which are transmitted by sandflies, cause a variety unknown. Rat1p also plays a role in transcription termi- of diseases throughout tropical and subtropical regions. All nation in yeast and mammalian cells (Kim et al. 2004; West of these parasites regulate their gene expression in order to et al. 2004), both through recruitment of polyadenylation adjust to the different conditions in the mammalian and factors and by digesting the cleaved product downstream of arthropod hosts—and all of them show no sign whatsoever the poly(A) site (Luo et al. 2006). This activity cannot be of gene-specific control of RNA polymerase II transcription complemented by nuclear-targeted Xrn1p, but a role for (Clayton 2002). The genomes of the Kinetoplastids are Xrn1p was nevertheless suggested by the fact that deletion constructed of polycistronic transcription units that can be of XRN1 exacerbated the Rat1 mutant phenotype. over 1000 kb long and produce hundreds of independently The study of XRN homologs in multicellular eukaryotes regulated mRNAs (Berriman 2005; El-Sayed et al. 2005a). has revealed functions similar to those seen in yeast. 59/39 Although transcription probably initiates in the gaps exonuclease activity was demonstrated for the mouse between polycistronic units, specific initiation sites have (Bashkirov et al. 1997) and Arabidopsis (Kastenmeier and proved elusive (Martinez-Calvillo et al. 2003, 2004). In- Green 2000) homologs. A requirement for 59/39 mRNA dividual mRNAs are excised from the polycistronic pre- degradation in Caenorhabditis elegans was demonstrated by cursors by 59-trans splicing and polyadenylation (Liang RNA silencing of xrn-1; this resulted in a failure of ventral et al. 2003). The levels of the encoded proteins are epithelial closure (Newbury and Woolard 2004). The determined primarily through regulation of mRNA turn- mRNA encoding the Drosophila homolog, pacman,isan over and translation and protein degradation (Clayton abundant component of maternal mRNA in embryos, 2002). again suggesting a role in development; this enzyme can We have particularly concentrated on the regulation of the complement the yeast Dxrn1 mutant, indicating functional turnover of two mRNAs, which are expressed almost exclu- conservation from Drosophila to yeast (Till et al. 1998).
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