The 5S RNP Couples p53 Homeostasis to Ribosome Biogenesis and Nucleolar Stress

Sloan, Katherine E.; Bohnsack, Markus T.; Watkins, Nicholas J.

doi:10.1016/j.celrep.2013.08.049

Cited by 259 publications

(315 citation statements)

References 39 publications

(49 reference statements)

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“…m 5 C modifications can be installed by any of the seven proteins of the Nol1/Nop2/SUN domain (NSUN) family and by an enzyme named DNA methyltransferase 2 (DNMT2). DNMT2 mainly catalyses the m 5 C modification in position 38 of tRNA Asp in human cells (Goll et al , 2006), while the so far characterised NSUN proteins show specificity for tRNAs (NSUN2, NSUN6; Schaefer et al , 2010; Tuorto et al , 2012; Blanco et al , 2014; Haag et al , 2015a) or rRNA (NSUN1/NOP2, NSUN5; Sloan et al , 2013; Tafforeau et al , 2013; Schosserer et al , 2015). NSUN2 can also modify vault RNAs and mRNAs (Hussain et al , 2013), and NSUN4 was described to localise to mitochondria where it was shown to methylate the mitochondrial 12S rRNA in mice (Cámara et al , 2011; Metodiev et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

et al. 2016

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Mitochondrial gene expression uses a non‐universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt‐)tRNAM et mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt‐tRNAM et to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease. We further identify ALKBH1/ABH1 as the dioxygenase responsible for oxidising m5C34 of mt‐tRNAM et to generate an f5C34 modification. In vitro codon recognition studies with mitochondrial translation factors reveal preferential utilisation of m5C34 mt‐tRNA Met in initiation. Depletion of either NSUN3 or ABH1 strongly affects mitochondrial translation in human cells, implying that modifications generated by both enzymes are necessary for mt‐tRNAM et function. Together, our data reveal how modifications in mt‐tRNAM et are generated by the sequential action of NSUN3 and ABH1, allowing the single mitochondrial tRNAM et to recognise the different codons encoding methionine.

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Section: Introductionmentioning

confidence: 99%

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

et al. 2016

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“…Although the target spectrum of these family members is less well studied, the yeast homologs of NSUN1 and NSUN5, Nop2 and Rcm1, have been shown to methylate residues in the 28S ribosomal RNA at positions C2870 and C2278, respectively . In humans, knockdown of NSUN1 causes severe pre-rRNA processing defects, whereas depletion of NSUN5 leads to only mild defects in the biogenesis of the large ribosomal subunit (Sloan et al 2013;Tafforeau et al 2013;Schosserer et al 2015). Another member of the NSUN family, NSUN4 was recently found to localize to mitochondria and to methylate C911 in the mitochondrial 12S rRNA in mice (Metodiev et al 2014).…”

Section: Introductionmentioning

confidence: 99%

NSUN6 is a human RNA methyltransferase that catalyzes formation of m⁵C72 in specific tRNAs

Haag

Warda

Kretschmer

et al. 2015

RNA

161

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Many cellular RNAs require modification of specific residues for their biogenesis, structure, and function. 5-methylcytosine (m 5 C) is a common chemical modification in DNA and RNA but in contrast to the DNA modifying enzymes, only little is known about the methyltransferases that establish m 5 C modifications in RNA. The putative RNA methyltransferase NSUN6 belongs to the family of Nol1/Nop2/SUN domain (NSUN) proteins, but so far its cellular function has remained unknown. To reveal the target spectrum of human NSUN6, we applied UV crosslinking and analysis of cDNA (CRAC) as well as chemical crosslinking with 5-azacytidine. We found that human NSUN6 is associated with tRNAs and acts as a tRNA methyltransferase. Furthermore, we uncovered tRNA Cys and tRNA Thr as RNA substrates of NSUN6 and identified the cytosine C72 at the 3 ′ end of the tRNA acceptor stem as the target nucleoside. Interestingly, target recognition in vitro depends on the presence of the 3 ′ -CCA tail. Together with the finding that NSUN6 localizes to the cytoplasm and largely colocalizes with marker proteins for the Golgi apparatus and pericentriolar matrix, our data suggest that NSUN6 modifies tRNAs in a late step in their biogenesis.

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“…Furthermore, a comprehensive understanding of ribosome production in human cells is very important, as ribosome biogenesis is coupled to the regulation of the tumor suppressor p53 via MDM2 and p14 ARF and directly linked to the regulation of cellular proliferation (Stumpf and Ruggero 2011;Sloan et al 2013a).…”

Section: Introductionmentioning

confidence: 99%

The roles of SSU processome components and surveillance factors in the initial processing of human ribosomal RNA

Sloan

Bohnsack

Schneider

et al. 2014

RNA

102

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During eukaryotic ribosome biogenesis, three of the mature ribosomal (r)RNAs are released from a single precursor transcript (pre-rRNA) by an ordered series of endonucleolytic cleavages and exonucleolytic processing steps. Production of the 18S rRNA requires the removal of the 5 ′ external transcribed spacer (5 ′ ETS) by endonucleolytic cleavages at sites A0 and A1/site 1. In metazoans, an additional cleavage in the 5 ′ ETS, at site A ′ , upstream of A0, has also been reported. Here, we have investigated how A ′ processing is coordinated with assembly of the early preribosomal complex. We find that only the tUTP (UTP-A) complex is critical for A ′ cleavage, while components of the bUTP (UTP-B) and U3 snoRNP are important, but not essential, for efficient processing at this site. All other factors involved in the early stages of 18S rRNA processing that were tested here function downstream from this processing step. Interestingly, we show that the RNA surveillance factors XRN2 and MTR4 are also involved in A ′ cleavage in humans. A ′ cleavage is largely bypassed when XRN2 is depleted, and we also discover that A ′ cleavage is not always the initial processing event in all cell types. Together, our data suggest that A ′ cleavage is not a prerequisite for downstream pre-rRNA processing steps and may, in fact, represent a quality control step for initial pre-rRNA transcripts. Furthermore, we show that components of the RNA surveillance machinery, including the exosome and TRAMP complexes, also play key roles in the recycling of excised spacer fragments and degradation of aberrant pre-rRNAs in human cells.

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The 5S RNP Couples p53 Homeostasis to Ribosome Biogenesis and Nucleolar Stress

Cited by 259 publications

References 39 publications

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

NSUN6 is a human RNA methyltransferase that catalyzes formation of m⁵C72 in specific tRNAs

The roles of SSU processome components and surveillance factors in the initial processing of human ribosomal RNA

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The 5S RNP Couples p53 Homeostasis to Ribosome Biogenesis and Nucleolar Stress

Cited by 259 publications

References 39 publications

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA Met to expand codon recognition in mitochondrial translation

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA Met to expand codon recognition in mitochondrial translation

NSUN6 is a human RNA methyltransferase that catalyzes formation of m5C72 in specific tRNAs

The roles of SSU processome components and surveillance factors in the initial processing of human ribosomal RNA

Contact Info

Product

Resources

About

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

NSUN 3 and ABH 1 modify the wobble position of mt‐t RNA ^Met to expand codon recognition in mitochondrial translation

NSUN6 is a human RNA methyltransferase that catalyzes formation of m⁵C72 in specific tRNAs