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

janelia7_blocks-janelia7_biblio_header | block

eLife. 2023 Aug 02;12. doi: 10.7554/eLife.75628

Gessner S, Martin ZA, Reiche MA, Santos JA, Dinkele R, Ramudzuli A, Dhar N, de Wet TJ, Anoosheh S, Lang DM, Aaron J, Chew T, Herrmann J, Müller R, McKinney JD, Woodgate R, Mizrahi V, Venclovas Č, Lamers MH, Warner DF

janelia7_blocks-janelia7_biblio_abstract | block

Abstract

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in 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 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.

PMID: 37530405 [PubMed - indexed for MEDLINE]

node:body | entity_field

bioRxiv PrePrint https://doi.org/10.1101/2021.11.16.468908

janelia7_blocks-janelia7_biblio_authors | block

janelia7_blocks-janelia7_biblio_tools | block

Main Menu (Mobile)- Block

Main Menu - Block

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

Abstract

PMID: 37530405 [PubMed - indexed for MEDLINE]

Janelia Authors