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Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome
A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polym...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421592/ https://www.ncbi.nlm.nih.gov/pubmed/37530405 http://dx.doi.org/10.7554/eLife.75628 |
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author | Gessner, Sophia Martin, Zela Alexandria-Mae Reiche, Michael A Santos, Joana A Dinkele, Ryan Ramudzuli, Atondaho Dhar, Neeraj de Wet, Timothy J Anoosheh, Saber Lang, Dirk M Aaron, Jesse Chew, Teng-Leong Herrmann, Jennifer Müller, Rolf McKinney, John D Woodgate, Roger Mizrahi, Valerie Venclovas, Česlovas Lamers, Meindert H Warner, Digby F |
author_facet | Gessner, Sophia Martin, Zela Alexandria-Mae Reiche, Michael A Santos, Joana A Dinkele, Ryan Ramudzuli, Atondaho Dhar, Neeraj de Wet, Timothy J Anoosheh, Saber Lang, Dirk M Aaron, Jesse Chew, Teng-Leong Herrmann, Jennifer Müller, Rolf McKinney, John D Woodgate, Roger Mizrahi, Valerie Venclovas, Česlovas Lamers, Meindert H Warner, Digby F |
author_sort | Gessner, Sophia |
collection | PubMed |
description | A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III β subunit (β clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuB(AAAAGG) mutant containing a disrupted β clamp-binding motif abolishes ImuB–β clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this β clamp-binding antibiotic collapses pre-formed ImuB–β clamp complexes. These observations establish the essentiality of the ImuB–β clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance. |
format | Online Article Text |
id | pubmed-10421592 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-104215922023-08-12 Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome Gessner, Sophia Martin, Zela Alexandria-Mae Reiche, Michael A Santos, Joana A Dinkele, Ryan Ramudzuli, Atondaho Dhar, Neeraj de Wet, Timothy J Anoosheh, Saber Lang, Dirk M Aaron, Jesse Chew, Teng-Leong Herrmann, Jennifer Müller, Rolf McKinney, John D Woodgate, Roger Mizrahi, Valerie Venclovas, Česlovas Lamers, Meindert H Warner, Digby F eLife Biochemistry and Chemical Biology A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III β subunit (β clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuB(AAAAGG) mutant containing a disrupted β clamp-binding motif abolishes ImuB–β clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this β clamp-binding antibiotic collapses pre-formed ImuB–β clamp complexes. These observations establish the essentiality of the ImuB–β clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance. eLife Sciences Publications, Ltd 2023-08-02 /pmc/articles/PMC10421592/ /pubmed/37530405 http://dx.doi.org/10.7554/eLife.75628 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) . |
spellingShingle | Biochemistry and Chemical Biology Gessner, Sophia Martin, Zela Alexandria-Mae Reiche, Michael A Santos, Joana A Dinkele, Ryan Ramudzuli, Atondaho Dhar, Neeraj de Wet, Timothy J Anoosheh, Saber Lang, Dirk M Aaron, Jesse Chew, Teng-Leong Herrmann, Jennifer Müller, Rolf McKinney, John D Woodgate, Roger Mizrahi, Valerie Venclovas, Česlovas Lamers, Meindert H Warner, Digby F Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome |
title | Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome |
title_full | Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome |
title_fullStr | Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome |
title_full_unstemmed | Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome |
title_short | Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome |
title_sort | investigating the composition and recruitment of the mycobacterial imua′–imub–dnae2 mutasome |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421592/ https://www.ncbi.nlm.nih.gov/pubmed/37530405 http://dx.doi.org/10.7554/eLife.75628 |
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