A novel protein, Pho92, has a conserved YTH domain and regulates phosphate metabolism by decreasing the mRNA stability of <i>PHO4</i> in <i>Saccharomyces cerevisiae</i>

Kang, Hyun Jun; Jeong, Sook Jin; Kim, Kyung Nam; Baek, In Joon; Chang, Miwha; Kang, Chang Min; Park, Yong Sung; Yun, Cheol Won

doi:10.1042/bj20130862

Cited by 52 publications

(58 citation statements)

References 43 publications

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“…Therefore, these proteins may not be able to recognize m 6 A with good affinity. This is supported by our mutagenesis studies (see below) and the fact that YTHDC1 failed to complement the function of MRB1 in yeast, whereas YTHDF2 was able to complement (14).…”

Section: Resultssupporting

confidence: 67%

“…The N-terminal regions of these proteins are poorly conserved, although that of YTHDF2 mediates its function in regulating mRNA localization and degradation (7). Yeast MRB1 regulates phosphate metabolism by destabilizing the mRNA of a transcription factor of the pathway and, hence, it is also known as Pho92 (14), although direct evidence of MRB1 regulating m 6 A-containing mRNAs in yeast cells is lacking.…”

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confidence: 99%

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Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain

Luo

Tong

2014

Proc. Natl. Acad. Sci. U.S.A.

209

237

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Methylation of the N6 position of selected internal adenines (m 6 A) in mRNAs and noncoding RNAs is widespread in eukaryotes, and the YTH domain in a collection of proteins recognizes this modification. We report the crystal structure of the splicing factor YT521-B homology (YTH) domain of Zygosaccharomyces rouxii MRB1 in complex with a heptaribonucleotide with an m 6 A residue in the center. The m 6 A modification is recognized by an aromatic cage, being sandwiched between a Trp and Tyr residue and with the methyl group pointed toward another Trp residue. Mutations of YTH domain residues in the RNA binding site can abolish the formation of the complex, confirming the structural observations. These residues are conserved in the human YTH proteins that also bind m 6 A RNA, suggesting a conserved mode of recognition. Overall, our structural and biochemical studies have defined the molecular basis for how the YTH domain functions as a reader of methylated adenines.T he methylation of the N6 position of selected internal adenines (m 6 A) modification is widespread in eukaryotic mRNAs and noncoding RNAs (1-3), reviewed in refs. 4-6. Recent studies have linked this modification to the regulation of alternative splicing (2), RNA processing, and mRNA degradation (7). Although the exact cellular functions of this modification are still not completely understood, m 6 A has been linked to the regulation of the circadian clock (8) and m 6 A levels are highest during yeast meiosis (1). The m 6 A methyl group can be removed by the dioxygenases FTO (9) and ALKBH5 (10, 11), suggesting that m 6 A is a reversible modification on the RNA.A consensus sequence G(m 6 A)C has been identified for this modification based on transcriptome-wide mapping (1, 2), which is consistent with that identified from earlier biochemical studies (4-6). Several YTH domain (12) family members, YTHDF1, YTHDF2, and YTHDF3 in humans (2, 7) and methylated RNAbinding protein 1 (MRB1) in yeast (1), have been shown to bind RNAs with m 6 A modification, and the binding consensus for the YTH domain of YTHDF2 is also G(m 6 A)C (7), consistent with that found by transcriptome-wide mapping.The YTH domain contains ∼160 residues and is found in yeast, plants, and animals ( Fig. S1) (12, 13). The domain is located at the C-terminal end of yeast MRB1 and human YTHDF1-3 (Fig. 1A), and its sequence is well conserved among these proteins (Fig. 1B and Fig. S1). The N-terminal regions of these proteins are poorly conserved, although that of YTHDF2 mediates its function in regulating mRNA localization and degradation (7). Yeast MRB1 regulates phosphate metabolism by destabilizing the mRNA of a transcription factor of the pathway and, hence, it is also known as Pho92 (14), although direct evidence of MRB1 regulating m 6 A-containing mRNAs in yeast cells is lacking.The structures of the YTH domains of two related proteins, human YTH domain containing protein 1 [YTHDC1; Protein Data Bank (PDB) ID code 2YUD] and YTHDC2 (2YU6), have been reported. Human YTHDC1 has 29% sequence i...

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Section: Resultssupporting

confidence: 67%

mentioning

confidence: 99%

Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain

Luo

Tong

2014

Proc. Natl. Acad. Sci. U.S.A.

209

237

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“…As the first step of mRNA decay, deadenylation is first carried out by the Pan2-Pan3 complex and further digested by the Ccr4-Not complex (for review, see Norbury 2013). Some RBPs, like the PUFs, are known to activate degradation of target mRNAs through their interaction with Pop2p, a member of the Ccr4-Not complex (Goldstrohm et al 2006;Kang et al 2014). After deadenylation, mRNA may be degraded by the exosome or decapped by Dcp1p/ Dcp2p, which are recruited by the Pat1-Lsm1-Lsm7 complex (Bouveret et al 2000;Tharun et al 2000;Coller and Parker 2004).…”

Section: Introductionmentioning

confidence: 99%

The Rtr1p CTD phosphatase autoregulates its mRNA through a degradation pathway involving the REX exonucleases

Hodko

Ward

Chanfreau

2016

RNA

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Rtr1p is a phosphatase that impacts gene expression by modulating the phosphorylation status of the C-terminal domain of the large subunit of RNA polymerase II. Here, we show that Rtr1p is a component of a novel mRNA degradation pathway that promotes its autoregulation through turnover of its own mRNA. We show that the 3 ′ UTR of the RTR1 mRNA contains a cis element that destabilizes this mRNA. RTR1 mRNA turnover is achieved through binding of Rtr1p to the RTR1 mRNP in a manner that is dependent on this cis element. Genetic evidence shows that Rtr1p-mediated decay of the RTR1 mRNA involves the 5 ′ -3 ′ DExD/H-box RNA helicase Dhh1p and the 3 ′ -5 ′ exonucleases Rex2p and Rex3p. Rtr1p and Rex3p are found associated with Dhh1p, suggesting a model for recruiting the REX exonucleases to the RTR1 mRNA for degradation. Rtr1p-mediated decay potentially impacts additional transcripts, including the unspliced BMH2 pre-mRNA. We propose that Rtr1p may imprint its RNA targets cotranscriptionally and determine their downstream degradation mechanism by directing these transcripts to a novel turnover pathway that involves Rtr1p, Dhh1p, and the REX family of exonucleases.

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“…Later on, several groups reported that the YTH domain-containing proteins specifically bind m 6 A RNA (5,8,20) and that YTHDF2 destabilizes its targeted mRNA by its interaction with m 6 A (20). The only known YTH domain-containing protein in Saccharomyces cerevisiae Pho92 also decreases the Pho4 mRNA stability by binding to its 3Ј-UTR during the phosphate metabolism (21). Very recently, it was reported that the association of YTHDF1 with m 6 A RNA regulates the mRNA translation efficiency (22).…”

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confidence: 99%

Structural Basis for the Discriminative Recognition of N6-Methyladenosine RNA by the Human YT521-B Homology Domain Family of Proteins

Liu

Ahmed

et al. 2015

Journal of Biological Chemistry

271

312

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A novel protein, Pho92, has a conserved YTH domain and regulates phosphate metabolism by decreasing the mRNA stability of PHO4 in Saccharomyces cerevisiae

Cited by 52 publications

References 43 publications

Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain

Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain

The Rtr1p CTD phosphatase autoregulates its mRNA through a degradation pathway involving the REX exonucleases

Structural Basis for the Discriminative Recognition of N6-Methyladenosine RNA by the Human YT521-B Homology Domain Family of Proteins

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