Dataset Information

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

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.

SUBMITTER: Gessner S

PROVIDER: S-EPMC10421592 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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

Gessner Sophia S Martin Zela Alexandria-Mae ZA Reiche Michael A MA Santos Joana A JA Dinkele Ryan R Ramudzuli Atondaho A Dhar Neeraj N de Wet Timothy J TJ Anoosheh Saber S Lang Dirk M DM Aaron Jesse J Chew Teng-Leong TL Herrmann Jennifer J Müller Rolf R McKinney John D JD Woodgate Roger R Mizrahi Valerie V Venclovas Česlovas Č Lamers Meindert H MH Warner Digby F DF

eLife 20230802

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in <i>Mycobacterium tuberculosis</i> 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 ...[more]

PMID: 37530405

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Project description:IntroductionAlthough the sustainability of the health workforce has been identified as essential to achieving health and wider development objectives, challenges with securing and retaining the healthcare workforce persist. In the UK, there are notable shortages across a wide range of National Health Service (NHS) staff groups, with a high staff turnover indicating retention issues in the healthcare workforce. In addition, gaps exist in understanding the root cause of individual organisation's workforce deficiencies and how their practice environment factors interact to impact workforce recruitment and retention.Methods and analysisAn exploratory mixed-methods approach will be conducted to investigate the impact of organisational practice environment factors on healthcare workforce recruitment and retention in two Integrated Care Systems (ICS) in the East of England. We will conduct an online survey of newly qualified and established nurses and allied health professionals using a questionnaire adapted from two validated instruments. Our calculation suggests a sample size of 373 participants, we will aim to surpass this in our recruitment to strengthen the statistical analyses. Multilevel linear regression models will be fitted to evaluate the association between organisational practice environmental factors and staff recruitment and retention. The qualitative interviews will explore the experiences and perspectives of staff and senior leaders to explain the survey results and any significant associations therein. Also, the interviews will explore how to strengthen the partnership between higher education institutions, Health Education England, health and care service providers, NHS nursing and allied health professional staff to enhance recruiting and retaining staff. An exploratory inductive coding and analysis will follow Braun and Clarke's recommendations to generate key themes from transcribed interview data.Ethics and disseminationEthical approval has been obtained through the University of Suffolk Research Ethics Committee (approval number: RETH(S)22/051). Findings from our work will be disseminated through publications in peer-reviewed journals; presentations at stakeholders' events, professional and academic conferences; and short reports for stakeholders, including participating ICSs.

Dataset Information

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

Publications

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

Similar Datasets

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