Genetic investigation of formaldehyde-induced DNA damage response in Schizosaccharomyces pombe

Anandarajan, Vinesh; Noguchi, Chiaki; Oleksak, Julia; Grothusen, Grant; Terlecky, Daniel; Noguchi, Eishi

doi:10.1007/s00294-020-01057-z

Cited by 17 publications

(8 citation statements)

References 48 publications

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“…BP–3′ss intervening segments in several introns were predicted to fold into secondary structures with shorter effective distances between the BP and 3′ss. Such secondary structures were detected in, for example, intron 1 of cam1 [encoding calmodulin ( 35 )], intron 1 of ste4 [encoding MAPK cascade adaptor protein ( 36 )], intron 2 of fmd1 [encoding formaldehyde dehydrogenase ( 37 )], intron 1 of whi5 [encoding a transcription repressor ( 38 )], intron 2 of atg20 [encoding an autophagy protein ( 39 )] and intron 2 of mug65 [encoding a dysferlin-like membrane trafficking factor ( 40 )] ( Supplementary Figures S6 and S7A ). In such cases, the disruption of secondary structures by exposure to elevated temperatures could open the fold and increase the distance between the BP and 3′ss.…”

Section: Resultsmentioning

confidence: 99%

“…We report that Sde2, Cay1 and Tls1 control gene expression and alternative splicing of selected chromatin and RNAi factors in S. pombe . We and others have shown that their mutants are defective in heterochromatin silencing and genomic instability ( 22 , 37 , 42 , 45 , 47 , 78 ). RNAi defects in the sde2 mutant have also been reported ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

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Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2

Anil

Choudhary

Pandian

et al. 2022

Nucleic Acids Research

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Intron diversity facilitates regulated gene expression and alternative splicing. Spliceosomes excise introns after recognizing their splicing signals: the 5′-splice site (5′ss), branchpoint (BP) and 3′-splice site (3′ss). The latter two signals are recognized by U2 small nuclear ribonucleoprotein (snRNP) and its accessory factors (U2AFs), but longer spacings between them result in weaker splicing. Here, we show that excision of introns with a BP-distant 3′ss (e.g. rap1 intron 2) requires the ubiquitin-fold-activated splicing regulator Sde2 in Schizosaccharomyces pombe. By monitoring splicing-specific ura4 reporters in a collection of S. pombe mutants, Cay1 and Tls1 were identified as additional regulators of this process. The role of Sde2, Cay1 and Tls1 was further confirmed by increasing BP–3′ss spacings in a canonical tho5 intron. We also examined BP-distant exons spliced independently of these factors and observed that RNA secondary structures possibly bridged the gap between the two signals. These proteins may guide the 3′ss towards the spliceosome's catalytic centre by folding the RNA between the BP and 3′ss. Orthologues of Sde2, Cay1 and Tls1, although missing in the intron-poor Saccharomyces cerevisiae, are present in intron-rich eukaryotes, including humans. This type of intron-specific pre-mRNA splicing appears to have evolved for regulated gene expression and alternative splicing of key heterochromatin factors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2

Anil

Choudhary

Pandian

et al. 2022

Nucleic Acids Research

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“…Such acetaldehyde‐induced DNA adducts may include ICLs and DPCs, which must be removed by DNA repair mechanisms. Although mechanisms of DPC repair are less understood [ 12 , 49 ], it is known that ICL repair requires the FA DNA repair pathway [ 4 , 5 ]. Consistently, loss of the FA pathway is reported to cause acetaldehyde sensitivity and genomic instability in response to acetaldehyde [ 10 , 11 , 15 , 16 , 17 , 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although these monoadducts themselves may cause problems during DNA transactions, PdG adducts can generate more toxic lesions including DNA ICLs and DNA–protein crosslinks (DPCs) [ 6 ]. ICLs and DPCs interfere with the DNA replication and repair processes, leading to genomic instability, which is a hallmark of cancer [ 6 , 8 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

FANCD2 limits acetaldehyde‐induced genomic instability during DNA replication in esophageal keratinocytes

et al. 2021

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“…Formaldehyde dehydrogenase is critical to minimize the DPC issue, and gene knockout organisms are commonly used to study the intracellular pathological changes of formaldehyde [18,21,22] . DPCs mainly consist of ribosomes and outer membrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Comparative Transcriptome and Metabolome Analyses Reveal the Methanol Dissimilation Pathway of Pichia Pastoris

Yu¹,

Yang²,

Zhao³

et al. 2021

Preprint

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Background: Pichia pastoris (Komagataella phaffii) is a model organism widely used for the recombinant expression of eukaryotic proteins, and it can metabolize methanol as its sole carbon and energy source. Methanol is oxidized to formaldehyde by alcohol oxidase (AOX), which is further metabolized either in the assimilation or dissimilation pathway. In the dissimilation pathway, formaldehyde is oxidized to CO2 by formaldehyde dehydrogenase (FLD), S-hydroxymethyl glutathione hydrolase (FGH) and formate dehydrogenase (FDH). In addition, formaldehyde induces DNA-protein crosslinks (DPCs). Formaldehyde dehydrogenase is critical to minimize formaldehyde-mediated DNA lesions. Although phenotypes have been studied in engineered strains by modified dissimilation, there is a clear lack of systematic studies at the whole-omics level, especially transcriptomics and metabolomics.Results: Focusing on the dissimilation pathway being cut off, we compared the transcriptomes and metabolomes from a formaldehyde dehydrogenase-deficient strain (Δfld), an S-hydroxymethyl glutathione dehydrogenase-deficient strain (Δfgh), a formate dehydrogenase deficient-strain (Δfdh) and the wild type (GS115). First, the differences between strains were most apparent after FLD knockout. When methanol was used as the sole carbon source, the differential metabolites between GS115 and Δfld were mainly enriched in ABC transporters, amino acid biosynthesis, and protein digestion and absorption. Second, analysis of differentially expressed genes (DEGs) between knockout and wild type strains under methanolic incubation showed that oxidative phosphorylation, glycolysis and the TCA cycle were downregulated, while proteasomes, autophagy and peroxisomes were upregulated. Transcription of alcohol metabolism was upregulated. It is worth noting that the degree of variation was positively correlated with the gene order of dissimilation pathway knockdown. In addition, there were significant differences in amino acid metabolism and glutathione redox cycling that raised our concerns about formaldehyde sorption in cells.Conclusions: This is the first time that integrity of dissimilation pathway analysis was carried out in Pichia pastoris on the basis of transcriptomics and metabolomics. Truncation of the dissimilation pathway affected methanol metabolism, and knockdown of FLD impaired formaldehyde assimilation. The significant downregulation of oxidative phosphorylation may reveal that FLD and FGH are key enzymes in the energy utilization of cellular methanol metabolism. In addition, formaldehyde can not only bind glutathione but also react with amino acids, especially cysteine. The upregulation of the proteasome and autophagy may solve the problem of DNA-protein crosslinking caused by formaldehyde.

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Genetic investigation of formaldehyde-induced DNA damage response in Schizosaccharomyces pombe

Cited by 17 publications

References 48 publications

Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2

Splicing of branchpoint-distant exons is promoted by Cactin, Tls1 and the ubiquitin-fold-activated Sde2

FANCD2 limits acetaldehyde‐induced genomic instability during DNA replication in esophageal keratinocytes

Comparative Transcriptome and Metabolome Analyses Reveal the Methanol Dissimilation Pathway of Pichia Pastoris

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