Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB

Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome. Gessner, S., Martin, Z. A., Reiche, M. A, Santos, J. A, Dinkele, R., Ramudzuli, A., Dhar, N., de Wet, T. J, Anoosheh, S., Lang, D. M, Aaron, J., Chew, T., Herrmann, J., Müller, R., McKinney, J. D, Woodgate, R., Mizrahi, V., Venclovas, Č., Lamers, M. H, & Warner, D. F eLife, 12:e75628, eLife Sciences Publications, Ltd, 2023.

Paper doi abstract bibtex

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 imuBAAAAGG 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.

@article{Gessner2023,
abstract = {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 $\beta$ subunit ($\beta$ clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuBAAAAGG mutant containing a disrupted $\beta$ clamp-binding motif abolishes ImuB–$\beta$ clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this $\beta$ clamp-binding antibiotic collapses pre-formed ImuB–$\beta$ clamp complexes. These observations establish the essentiality of the ImuB–$\beta$ 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.},
author = {Gessner, Sophia and Martin, Zela Alexandria-Mae and Reiche, Michael A and Santos, Joana A and Dinkele, Ryan and Ramudzuli, Atondaho and Dhar, Neeraj and de Wet, Timothy J and Anoosheh, Saber and Lang, Dirk M and Aaron, Jesse and Chew, Teng-Leong and Herrmann, Jennifer and M{\"{u}}ller, Rolf and McKinney, John D and Woodgate, Roger and Mizrahi, Valerie and Venclovas, {\v{C}}eslovas and Lamers, Meindert H and Warner, Digby F},
doi = {10.7554/eLife.75628},
editor = {Stallings, Christina L and Soldati-Favre, Dominique},
issn = {2050-084X},
journal = {eLife},
keywords = {Mycobacterium smegmatis,Mycobacterium tuberculosis,OA,OA{\_}PMC,anti-evolution,antibiotic resistance,fund{\_}not{\_}ack,induced mutagenesis,mutasome,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
pages = {e75628},
pmid = {37530405},
publisher = {eLife Sciences Publications, Ltd},
title = {{Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome}},
url = {https://doi.org/10.7554/eLife.75628},
volume = {12},
year = {2023}
}

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