Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome
Year: 2023
Type: article
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 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.
Source: eLife
DOI: 10.7554/elife.75628
Authors: Sophia Gessner, Zela Alexandria-Mae Martin, Michael A Reiche, Joana A Santos, Ryan Dinkele, Atondaho Ramudzuli, Neeraj Dhar, Timothy J de Wet, Saber Anoosheh, Dirk M Lang, Jesse Aaron, Teng-Leong Chew, Jennifer Herrmann, Rolf Müller, John D McKinney, Roger Woodgate, Valerie Mizrahi, Česlovas Venclovas, Meindert H Lamers, Digby F Warner
Institutions: South African Medical Research Council, University of Cape Town, Institute of Infectious Disease and Molecular Medicine, École Polytechnique Fédérale de Lausanne, Howard Hughes Medical Institute, Leiden University Medical Center, University of Saskatchewan, Vaccine and Infectious Disease Organization, German Center for Infection Research, Helmholtz Centre for Infection Research, Helmholtz Institute for Pharmaceutical Research Saarland, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Wellcome Centre for Infectious Diseases Research in Africa, Vilnius University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Howard Hughes Medical Institute, David and Elaine Potter Foundation, National Research Foundation, South African Medical Research Council, Leids Universitair Medisch Centrum, Norges Forskningsråd, University of Cape Town, Medical Research Council, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W4385476382