D-Serine reduces the expression of the cytopathic genotoxin colibactin
Some Escherichia coli strains harbour the pks island, a 54 kb genomic island en-coding the biosynthesis genes for a genotoxic compound named colibactin. In eukaryotic cells, colibactin can induce DNA damage, cell cycle arrest and chro-mosomal instability. Production of colibactin has been implicated...
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| Format: | Article |
| Language: | English |
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Shared Science Publishers OG
2023-03-01
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| Series: | Microbial Cell |
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| Online Access: | http://microbialcell.com/researcharticles/2023a-hallam-microbial-cell/ |
| _version_ | 1797895380706263040 |
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| author | Jennifer C. Hallam Sofia Sandalli Iris Floria Natasha C. A. Turner Min Tang-Fichaux Eric Oswald Nicky O’Boyle Andrew J. Roe |
| author_facet | Jennifer C. Hallam Sofia Sandalli Iris Floria Natasha C. A. Turner Min Tang-Fichaux Eric Oswald Nicky O’Boyle Andrew J. Roe |
| author_sort | Jennifer C. Hallam |
| collection | DOAJ |
| description | Some Escherichia coli strains harbour the pks island, a 54 kb genomic island en-coding the biosynthesis genes for a genotoxic compound named colibactin. In eukaryotic cells, colibactin can induce DNA damage, cell cycle arrest and chro-mosomal instability. Production of colibactin has been implicated in the devel-opment of colorectal cancer (CRC). In this study, we demonstrate the inhibito-ry effect of D-Serine on the expression of the pks island in both prototypic and clinically-associated colibactin-producing strains and determine the implications for cytopathic effects on host cells. We also tested a comprehensive panel of proteinogenic L-amino acids and corresponding D-enantiomers for their ability to modulate clbB transcription. Whilst several D-amino acids exhibited the abil-ity to inhibit expression of clbB, D-Serine exerted the strongest repressing ac-tivity (>3.8-fold) and thus, we focussed additional experiments on D-Serine. To investigate the cellular effect, we investigated if repression of colibactin by D-Serine could reduce the cytopathic responses normally observed during infec-tion of HeLa cells with pks+ strains. Levels of γ-H2AX (a marker of DNA double strand breaks) were reduced 2.75-fold in cells infected with D-Serine treat-ment. Moreover, exposure of pks+ E. coli to D-Serine during infection caused a reduction in cellular senescence that was observable at 72 h post infection. The recent finding of an association between pks-carrying commensal E. coli and CRC, highlights the necessity for the development of colibactin targeting thera-peutics. Here we show that D-Serine can reduce expression of colibactin, and inhibit downstream cellular cytopathy, illuminating its potential to prevent colibactin-associated disease. |
| first_indexed | 2024-04-10T07:24:38Z |
| format | Article |
| id | doaj.art-f6988d7450664ab29a86b6de9c413c13 |
| institution | Directory Open Access Journal |
| issn | 2311-2638 |
| language | English |
| last_indexed | 2024-04-10T07:24:38Z |
| publishDate | 2023-03-01 |
| publisher | Shared Science Publishers OG |
| record_format | Article |
| series | Microbial Cell |
| spelling | doaj.art-f6988d7450664ab29a86b6de9c413c132023-02-24T09:31:22ZengShared Science Publishers OGMicrobial Cell2311-26382023-03-01103637710.15698/mic2023.03.793D-Serine reduces the expression of the cytopathic genotoxin colibactinJennifer C. Hallam0Sofia Sandalli1Iris Floria2Natasha C. A. Turner3Min Tang-Fichaux4Eric Oswald5Nicky O’Boyle6Andrew J. Roe7School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. IRSD, INSERM, INRAE, Université de Toulouse, ENVT, Toulouse, France.IRSD, INSERM, INRAE, Université de Toulouse, ENVT, Toulouse, France.School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom. Some Escherichia coli strains harbour the pks island, a 54 kb genomic island en-coding the biosynthesis genes for a genotoxic compound named colibactin. In eukaryotic cells, colibactin can induce DNA damage, cell cycle arrest and chro-mosomal instability. Production of colibactin has been implicated in the devel-opment of colorectal cancer (CRC). In this study, we demonstrate the inhibito-ry effect of D-Serine on the expression of the pks island in both prototypic and clinically-associated colibactin-producing strains and determine the implications for cytopathic effects on host cells. We also tested a comprehensive panel of proteinogenic L-amino acids and corresponding D-enantiomers for their ability to modulate clbB transcription. Whilst several D-amino acids exhibited the abil-ity to inhibit expression of clbB, D-Serine exerted the strongest repressing ac-tivity (>3.8-fold) and thus, we focussed additional experiments on D-Serine. To investigate the cellular effect, we investigated if repression of colibactin by D-Serine could reduce the cytopathic responses normally observed during infec-tion of HeLa cells with pks+ strains. Levels of γ-H2AX (a marker of DNA double strand breaks) were reduced 2.75-fold in cells infected with D-Serine treat-ment. Moreover, exposure of pks+ E. coli to D-Serine during infection caused a reduction in cellular senescence that was observable at 72 h post infection. The recent finding of an association between pks-carrying commensal E. coli and CRC, highlights the necessity for the development of colibactin targeting thera-peutics. Here we show that D-Serine can reduce expression of colibactin, and inhibit downstream cellular cytopathy, illuminating its potential to prevent colibactin-associated disease.http://microbialcell.com/researcharticles/2023a-hallam-microbial-cell/e. colicolibactinexpressiongenotoxincell-cycle |
| spellingShingle | Jennifer C. Hallam Sofia Sandalli Iris Floria Natasha C. A. Turner Min Tang-Fichaux Eric Oswald Nicky O’Boyle Andrew J. Roe D-Serine reduces the expression of the cytopathic genotoxin colibactin Microbial Cell e. coli colibactin expression genotoxin cell-cycle |
| title | D-Serine reduces the expression of the cytopathic genotoxin colibactin |
| title_full | D-Serine reduces the expression of the cytopathic genotoxin colibactin |
| title_fullStr | D-Serine reduces the expression of the cytopathic genotoxin colibactin |
| title_full_unstemmed | D-Serine reduces the expression of the cytopathic genotoxin colibactin |
| title_short | D-Serine reduces the expression of the cytopathic genotoxin colibactin |
| title_sort | d serine reduces the expression of the cytopathic genotoxin colibactin |
| topic | e. coli colibactin expression genotoxin cell-cycle |
| url | http://microbialcell.com/researcharticles/2023a-hallam-microbial-cell/ |
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