Investigating the composition and recruitment of the mycobacterial ImuA'-ImuB-DnaE2 mutasome

Gessner, S.; Martin, Z.A.M.; Reiche, M.A.; Santos, J.A.; Dinkele, R.; Ramudzuli, A.; ... ; Warner, D.F. (2023)

Article / Letter to editor

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 imuB(AAAAGG) 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.

• Mycobacterium tuberculosis
• Mycobacterium smegmatis
• induced mutagenesis
• antibiotic resistance
• anti-evolution
• mutasome
• Other

• All authors: Gessner, S.; Martin, Z.A.M.; Reiche, M.A.; Santos, J.A.; Dinkele, R.; Ramudzuli, A.; Dhar, N.; Wet, T.J. de; Anoosheh, S.; Lang, D.M.; Aaron, J.; Chew, T.L.; Herrmann, J.; Müller, R.; McKinney, J.D.; Woodgate, R.; Mizrahi, V.; Venclovas, C.; Lamers, M.H.; Warner, D.F.
• Date: 2023-08-02
• Journal: eLife
• Volume: 12
• DOI: doi:10.7554/eLife.75628
• Link: https://elifesciences.org/articles/75628