Publication

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

John McKinney, Neeraj Dhar, Zela Alexandria-Mae Martin
2023
Journal Articles

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 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.

Official source

https://infoscience.epfl.ch/entities/publication/d31c3625-7148-407a-b0b0-4760cdffa1f5

About this result

This page is automatically generated and may contain information that is not correct, complete, up-to-date, or relevant to your search query. The same applies to every other page on this website. Please make sure to verify the information with EPFL's official sources.

John McKinney, Neeraj Dhar, Zela Alexandria-Mae Martin
2023
Journal Articles

Abstract

Official source

https://infoscience.epfl.ch/entities/publication/d31c3625-7148-407a-b0b0-4760cdffa1f5

About this result

Related concepts (26)

Tuberculosis

Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in which case it is known as latent tuberculosis. Around 10% of latent infections progress to active disease which, if left untreated, kill about half of those affected. Typical symptoms of active TB are chronic cough with blood-containing mucus, fever, night sweats, and weight loss.

DNA repair

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes.

Mycobacterium tuberculosis

Mycobacterium tuberculosis (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M.

Related publications (31)

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania

Jacques Fellay, Zhi Ming Xu

The Mycobacterium tuberculosis complex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. We aim ...

Nature Portfolio2024

Single-cell analysis of the interactions between Mycobacterium tuberculosis and macrophages

Ophélie Rutschmann

Mycobacterium Tuberculosis is a highly effective pathogen infecting nearly a third of the world's population. An M. tuberculosis infection starts when droplets containing bacteria enter an individual's lungs. The first host cells to contact the bacteria ar ...

EPFL2024

Oxidative Defect Detection Within Free and Packed DNA Systems: A Quantum Mechanical/Molecular Mechanics (QM/ MM) Approach

Ursula Röthlisberger

Base excision repair enzymes (BERs) detect and repair oxidative DNA damage with efficacy despite the small size of the defects and their often only minor structural impact. A charge transfer (CT) model for rapid scanning of DNA stretches has been evoked to ...

Swiss Chemical Soc2024