RNase MRP and disease

Mattijssen, Sandy; Welting, T.; Pruijn, Ger J. M.

doi:10.1002/wrna.9

Cited by 53 publications

(75 citation statements)

References 107 publications

(175 reference statements)

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“…Accordingly, spawned by the extreme ubiquity of RNase P and the robustness of tRNA folding in vitro, RNase MRP, particularly in humans, has largely been dismissed by the literature as an analogous enzyme perhaps unable to teach us anything new about enzymatic RNPs. Like P, whose penchant for the tRNA-like fold has incited numerous RNAs to hijack P's cleavage activity through structural mimicry (for example, Wilusz et al 2012), MRP may have myriad substrates in various cellular contexts (Mattijssen et al 2010;Mercer et al 2011;Huang et al 2015), and our data do not preclude the possibility that other yet unrecognized essential substrates exist in human cells. However, the study of pretRNA cleavage was how RNase P's substrate recognition and enzymatic mechanism were elucidated (Altman and Smith 1971;Guthrie 1975;Guerrier-Takada et al 1983).…”

Section: Toward a Novel Rnp Cleavage Mechanismmentioning

confidence: 70%

“…The essential function of MRP RNA in human cells has remained controversial for >30 years (Mattijssen et al 2010). Here we provide genetic, cytological, and biochemical evidence that RNase MRP catalyzes at least one key step in the pre-rRNA processing cascade, the endonucleolytic cleavage that separates the 18S rRNA from the 5.8S-28S portion of the rRNA precursor.…”

Section: Discussionmentioning

confidence: 99%

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Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing

2017

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MRP RNA is an abundant, essential noncoding RNA whose functions have been proposed in yeast but are incompletely understood in humans. Mutations in the genomic locus for MRP RNA cause pleiotropic human diseases, including cartilage hair hypoplasia (CHH). Here we applied CRISPR-Cas9 genome editing to disrupt the endogenous human MRP RNA locus, thereby attaining what has eluded RNAi and RNase H experiments: elimination of MRP RNA in the majority of cells. The resulting accumulation of ribosomal RNA (rRNA) precursor-analyzed by RNA fluorescent in situ hybridization (FISH), Northern blots, and RNA sequencing-implicates MRP RNA in pre-rRNA processing. Amelioration of pre-rRNA imbalance is achieved through rescue of MRP RNA levels by ectopic expression. Furthermore, affinity-purified MRP ribonucleoprotein (RNP) from HeLa cells cleaves the human pre-rRNA in vitro at at least one site used in cells, while RNP isolated from cells with CRISPR-edited MRP loci loses this activity, and ectopic MRP RNA expression restores cleavage activity. Thus, a role for RNase MRP in human pre-rRNA processing is established. As demonstrated here, targeted CRISPR disruption is a valuable tool for functional studies of essential noncoding RNAs that are resistant to RNAi and RNase H-based degradation.

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Section: Toward a Novel Rnp Cleavage Mechanismmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing

2017

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“…First, PARN acts to promote the stability of only a subpopulation of these RNAs, and therefore, the effect on steady-state levels is not significant. Second, PARN deadenylates the majority of these RNA populations, but the lack of PARN depletion is not sufficient to trigger the decay of these RNAs in a 3=-5= manner, possibly due to the presence of protective protein complexes, like the Lsm 2-8 complex for U6 snRNA or the Rpp20-Rpp25 complex for RMRP (39,40).…”

Section: Parn Removes Oligo(a) Tails From Y Rna 3= Ends Which Are Admentioning

confidence: 99%

PARN Modulates Y RNA Stability and Its 3′-End Formation

Shukla

Parker

2017

Molecular and Cellular Biology

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Loss-of-function mutations in 3=-to-5= exoribonucleases have been implicated in hereditary human diseases. For example, PARN mutations cause a severe form of dyskeratosis congenita (DC), wherein PARN deficiency leads to human telomerase RNA instability. Since the DC phenotype in PARN patients is even more severe than that of loss-of-function alleles in telomerase components, we hypothesized that PARN would also be required for the stability of other RNAs. Here, we show that PARN depletion reduces the levels of abundant human Y RNAs, which might contribute to the severe phenotype of DC observed in patients. Depletion of PAPD5 or the cytoplasmic exonuclease DIS3L rescues the effect of PARN depletion on Y RNA levels, suggesting that PARN stabilizes Y RNAs by removing oligoadenylated tails added by PAPD5, which would otherwise recruit DIS3L for Y RNA degradation. Through deep sequencing of 3= ends, we provide evidence that PARN can also deadenylate the U6 and RMRP RNAs without affecting their levels. Moreover, we observed widespread posttranscriptional oligoadenylation, uridylation, and guanylation of U6 and Y RNA 3= ends, suggesting that in mammalian cells, the formation of a 3= end for noncoding RNAs can be a complex process governed by the activities of various 3=-end polymerases and exonucleases.

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“…RNase MRP is an essential and evolutionarily conserved ribonucleoprotein complex that is responsible for the endonucleolytic cleavage at A3 in ITS1 (Lygerou et al 1996). Mutations in both the RNA and protein components of RNase MRP have been implicated to result in a compromised immune system and dwarfism (Mattijssen et al 2010). Cleavage at A3 initiates the formation of the 5 ′ end of 5.8S rRNA (Chu et al 1994;Henry et al 1994).…”

Section: Genetic Interaction With Rnase Mrpmentioning

confidence: 99%

The rRNA methyltransferase Bud23 shows functional interaction with components of the SSU processome and RNase MRP

Sardana

White

Johnson

2013

RNA

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Bud23 is responsible for the conserved methylation of G1575 of 18S rRNA, in the P-site of the small subunit of the ribosome. bud23Δ mutants have severely reduced small subunit levels and show a general failure in cleavage at site A2 during rRNA processing. Site A2 is the primary cleavage site for separating the precursors of 18S and 25S rRNAs. Here, we have taken a genetic approach to identify the functional environment of BUD23. We found mutations in UTP2 and UTP14, encoding components of the SSU processome, as spontaneous suppressors of a bud23Δ mutant. The suppressors improved growth and subunit balance and restored cleavage at site A2. In a directed screen of 50 ribosomal trans-acting factors, we identified strong positive and negative genetic interactions with components of the SSU processome and strong negative interactions with components of RNase MRP. RNase MRP is responsible for cleavage at site A3 in pre-rRNA, an alternative cleavage site for separating the precursor rRNAs. The strong negative genetic interaction between RNase MRP mutants and bud23Δ is likely due to the combined defects in cleavage at A2 and A3. Our results suggest that Bud23 plays a role at the time of A2 cleavage, earlier than previously thought. The genetic interaction with the SSU processome suggests that Bud23 could be involved in triggering disassembly of the SSU processome, or of particular subcomplexes of the processome.

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RNase MRP and disease

Cited by 53 publications

References 107 publications

Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing

Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing

PARN Modulates Y RNA Stability and Its 3′-End Formation

The rRNA methyltransferase Bud23 shows functional interaction with components of the SSU processome and RNase MRP

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