Secondary structure of RNase MRP RNA as predicted by phylogenetic comparison.

Schmitt, Michael N.; Bennett, Jeffery L.; Dairaghi, Daniel J.; Clayton, David A.

doi:10.1096/fasebj.7.1.7678563

Cited by 92 publications

(67 citation statements)

References 19 publications

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“…The other minor mutations were detected only in one or two Finnish families, as shown in Table 1. All mutations found in the Finnish CHH patients resided either in the evolutionally conserved nucleotides of the RMRP transcript 24,25 or disrupted the function of the promoter region. 12 The G262T mutation was not found among 173 anonymous Finnish blood donors, nor were the other minor mutations found among 120 of these controls and 160 non-Finnish controls.…”

Section: Resultsmentioning

confidence: 99%

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A→G mutation of the untranslated RMRP

et al. 2002

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Pleiotropic, recessively inherited cartilage-hair hypoplasia (CHH) is due to mutations in the untranslated RMRP gene on chromosome 9p13-p12 encoding the RNA component of RNase MRP endoribonuclease. We describe 36 different mutations in this gene in 91 Finnish and 44 non-Finnish CHH families. Based on their nature and localisation, these mutations can be classified into three categories: mutations affecting the promoter region, small changes of conserved nucleotides in the transcript, and insertions and duplications in the 5' end of the transcript. The only known functional region that seemed to avoid mutations was a nucleolar localisation signal region between nucleotides 23 -62. The most common mutation in CHH patients was a base substitution G for A at nucleotide 70. This mutation contributed 92% of the mutations in the Finnish CHH patients. Our results using linkage disequilibrium based maximum likelihood estimates with close markers, genealogical studies, and haplotype data suggested that the mutation was introduced to Finland some 3900 -4800 years ago, and before the expansion of the population. The same major mutation accounted for 48% of the mutations among CHH patients from other parts of Europe, North and South America, the Near East, and Australia. In the non-Finnish CHH families, the A70G mutation segregated with the same major haplotype, although shorter, as in most of the Finnish families. In 23 out of these 27 chromosomes, the common region extended over 60 kb, and, therefore, all the chromosomes most likely arose from a solitary event many thousands of years ago.

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Section: Resultsmentioning

confidence: 99%

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A→G mutation of the untranslated RMRP

et al. 2002

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“…The P3 domain of RNases P and MRP is composed of a conserved secondary structure with minimal conserved primary sequence Phylogenetic analyses of eukaryotic RNase P and RNase MRP RNA subunits have established refined secondary structure models for the entire RNase P RNA (Tranguch & Engelke, 1993) and somewhat less extensive models for RNase MRP RNA (Schmitt et al+, 1993;Pitulle et al+, 1998)+ A consensus structure for S. cerevisiae RNase P RNA is shown in Figure 1A+ One structural aspect common to the RNase P and MRP models is the existence of the P3 stem with an internal loop early in the RNA (nt 32-85 in S. cerevisiae RNA)+ Sequence comparison of RNase P and RNase MRP RNAs from a variety of species has identified residues that are widely conserved within species+ In contrast, there is little or no sequence conservation between the P3 internal loops of even the same enzyme in distant species+ Several nucleotide positions on the 59 side of the P3 internal loop are conserved between the RNase P and RNase MRP RNAs within a species+ Bold letters in Figure 1B indicate the positions that appear to be conserved between the RNase P and RNase MRP P3 domains within each species+ It had previously been noted (Tranguch & Engelke, 1993) in yeast that the lower P3 helix positions were more tightly conserved among RNase P RNAs than they appear to be between RNase P and RNase MRP+ Thus, it is possible that the loop and stem regions of the P3 domain serve different functions in RNase P+ The conservation of the P3 internal loop sequences between RNases P and MRP is entirely consistent with a specific interaction with one or more proteins common to RNase P and MRP+ If the same protein(s) bound to the P3 loop in both enzymes, the protein making direct contact would probably need to coevolve with both RNA subunits+…”

Section: Resultsmentioning

confidence: 99%

“…The P3 RNA domains from RNase P and RNase MRP were compared to provide a consensus structure+ P3 domains from the following species were used: S. cerevisiae and Schizosaccharomyces pombe RNase P (Tranguch & Engelke, 1993); human, mouse, and Xenopus laevis RNase P (Pitulle et al+, 1998); S. pombe RNase MRP (Paluh & Clayton, 1995); S. cerevisiae, human, mouse, and X. laevis RNase MRP (Schmitt et al+, 1993)+ Secondary structure is conserved throughout all species P3 domains in RNase P and RNase MRP; however there is very little primary sequence conservation among distant species (Fig+ 1B)+ Most intraspecies conservation between P3 domains from RNases P and MRP is located in the 59 side of the internal loop+ In the case of S. cerevisiae, there are seven internal loop P3 nucleotides that are identical in RNase P and RNase MRP (Fig+ 1B)+ However, four of the seven (U38, U39, C41, and A44) are also conserved between six different yeast species RNase P P3 domains previously sequenced (Tranguch & Engelke, 1993), suggesting the identity of these four nucleotides is important for the function of the P3 domain in yeast+…”

Section: Phylogenetic Analysis Of Rnase P and Rnase Mrp P3 Rna Domainsmentioning

confidence: 99%

“…P3 domain comparisons from RNase P and RNase MRP RNAs+ A: Secondary structure of S. cerevisiae RNase P RNA based on phylogenetic and biochemical analysis (Tranguch et al+, 1994)+ The location of the P3 RNA domain is shown in bold+ The location and sequence of the inserted hybridization tag (Bertrand et al+, 1998) between positions 133 and 139 is shown in italics+ B: P3 RNA domains from RNase P and MRP are shown from five eukaryotes, with intraspecies nucleotide conservations in bold+ S. cerevisiae and S. pombe RNase P sequence is from Tranguch & Engelke (1993) and Krupp et al+ (1986); human, mouse, and X. laevis RNase P is from Pitulle et al+ (1998); S. pombe RNase MRP is from Paluh and Clayton (1995); S. cerevisiae, human, mouse, and X. laevis RNase MRP is from Schmitt et al+ (1993)+ Engelke, 1993;Paluh & Clayton, 1995;Pitulle et al+, 1998)+ The P3 domains from Saccharomyces cerevisiae RNases P and MRP have been shown to be functionally equivalent, because swapping domains between enzymes was permitted (Lindahl et al+, 2000)+ Minimization experiments using domain deletions from yeast RNase P RNA have shown the P3 domain to be essential for generating a functional enzyme (PaganRamos et al+, 1994)+ Recent studies have further identified the P3 domain, in both human RNase P and RNase MRP, as required for binding the To antigen, a 40-kDa protein immunoprecipitated by human autoimmune sera (Reddy et al+, 1983;Liu et al+, 1994;Eder et al+, 1997)+ Microinjection experiments using synthetic RNase MRP RNA result in nucleolar localization of the RNA, consistent with the role of RNase MRP in processing prerRNA (Jacobson et al+, 1995)+ Microinjected RNase P RNA alone localized to the nucleolus only transiently (Jacobson et al+, 1997)+ Transient nucleolar localization of RNase P RNA was dependent on the P3 domain, suggesting a potential role for P3 in nucleolar localization+ It is currently not clear whether RNase P is also a nucleolar enzyme, and to what extent this is consistent among species+ Yeast nuclear RNase P appears largely nucleolar (Bertrand et al+, 1998), and in situ studies of mammalian RNase P have indicated either transient nucleolar association (Jacobson et al+, 1997) or limited steady-state localization to a "perinuclear compartment" (PNC) located on the nucleolar periphery (Matera et al+, 1995;Lee et al+, 1996)+ It has not been clear from these data whether the role of the P3 domain in localization is to direct holoenzyme assembly, which in turn causes localization, or whether the RNA interacts directly with some...…”

Section: Introductionmentioning

confidence: 99%

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An essential protein-binding domain of nuclear RNase P RNA

Ziehler

Morris

Scott

et al. 2001

RNA

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Eukaryotic RNase P and RNase MRP are endoribonucleases composed of RNA and protein subunits. The RNA subunits of each enzyme share substantial secondary structural features, and most of the protein subunits are shared between the two. One of the conserved RNA subdomains, designated P3, has previously been shown to be required for nucleolar localization. Phylogenetic sequence analysis suggests that the P3 domain interacts with one of the proteins common to RNase P and RNase MRP, a conclusion strengthened by an earlier observation that the essential domain can be interchanged between the two enzymes. To examine possible functions of the P3 domain, four conserved nucleotides in the P3 domain of Saccharomyces cerevisiae RNase P RNA (RPR1) were randomized to create a library of all possible sequence combinations at those positions. Selection of functional genes in vivo identified permissible variations, and viable clones that caused yeast to exhibit conditional growth phenotypes were tested for defects in RNase P RNA and tRNA biosynthesis. Under nonpermissive conditions, the mutants had reduced maturation of the RPR1 RNA precursor, an expected phenotype in cases where RNase P holoenzyme assembly is defective. This loss of RPR1 RNA maturation coincided, as expected, with a loss of pre-tRNA maturation characteristic of RNase P defects. To test whether mutations at the conserved positions inhibited interactions with a particular protein, specific binding of the individual protein subunits to the RNA subunit was tested in yeast using the threehybrid system. Pop1p, the largest subunit shared by RNases P and MRP, bound specifically to RPR1 RNA and the isolated P3 domain, and this binding was eliminated by mutations at the conserved P3 residues. These results indicate that Pop1p interacts with the P3 domain common to RNases P and MRP, and that this interaction is critical in the maturation of RNase P holoenzyme.

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“…Two-dimensional structures of S. cerevisiae MRP RNA and P RNA+ The structure of MRP RNA (A) is drawn according to Schmitt et al+ (1993), but is modified to accommodate our phylogenetic sequence analysis (data not shown)+ The structure of P RNA (B) is drawn according to Tranguch and Engelke (1993)+ Bases that are conserved between the two RNA molecules in S. cerevisiae are indicated by reverse contrast+ The molecules have been divided into Region 1 and Region 2+ Significant similarity of the two-dimensional structure is seen in Region 1 of the molecules, but not in Region 2+ The hairpins MRP3 and P3 are indicated by grey shading+ The inserts below each of the structures indicate the hairpins used to replace the S. cerevisiae MRP3 or P3 hairpins+ tures of Region 1 suggests that substructures in these regions may be functionally equivalent+ Hairpins MRP3 in MRP RNA and P3 in P RNA (Fig+ 1) present an example of similar structures that might perform identical functions+ To test this hypothesis, we constructed a hybrid gene (MRP-P3 Sc ) in which the sequence in the RRP2 (MRP RNA) gene encoding the MRP3 hairpin was replaced with the P3 sequence of the RPR1 (P RNA) gene+ The rest of the RRP2 gene, including flanking sequences, was unchanged+…”

Section: Resultsmentioning

confidence: 99%

Functional equivalence of hairpins in the RNA subunits of RNase MRP and RNase P in Saccharomyces cerevisiae

Lindahl

Fretz

Epps

et al. 2000

RNA

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RNase MRP and RNase P are both ribonucleoprotein enzymes performing endonucleolytic cleavage of RNA. RNase MRP cleaves at a specific site in the precursor-rRNA transcript to initiate processing of the 5.8S rRNA. RNase P cleaves precursor tRNAs to create the 59 end of the mature tRNAs. In spite of their different specificities, the two RNases have significant structural similarities. For example, the two enzymes in Saccharomyces cerevisiae share eight protein subunits; only one protein is unique to each enzyme. The RNA components of the two nucleases also show striking secondary-structure similarity. To begin to characterize the role of the RNA subunits in enzyme function and substrate specificity, we swapped two hairpin structures (MRP3 and P3) between RNase MRP RNA and RNase P RNA of S. cerevisiae. The hairpins in the two enzymes could be exchanged without loss of function or specificity. On the other hand, when the MRP3 hairpin in RNase MRP of S. cerevisiae was replaced with the corresponding hairpin from the RNA of Schizosaccharomyces pombe or human RNase MRP, no functional enzyme was assembled. We propose that the MRP3 and P3 hairpins in S. cerevisiae perform similar functions and have coevolved to maintain common features that are different from those of MRP3 and P3 hairpins in other species.

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Secondary structure of RNase MRP RNA as predicted by phylogenetic comparison.

Cited by 92 publications

References 19 publications

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A→G mutation of the untranslated RMRP

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A→G mutation of the untranslated RMRP

An essential protein-binding domain of nuclear RNase P RNA

Functional equivalence of hairpins in the RNA subunits of RNase MRP and RNase P in Saccharomyces cerevisiae

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