Regulation of the Expression of nucS, a Key Component of the Mismatch Repair System in Mycobacteria

TL;DR

This study explores how the nucS gene, involved in DNA repair in mycobacteria, is regulated, revealing insights into antibiotic resistance and evolutionary parallels with other DNA repair systems.

Contribution

The study identifies regulatory mechanisms of nucS in mycobacteria and reveals convergent evolution between canonical and non-canonical DNA repair pathways.

Findings

nucS expression declines during stationary phase in Mycobacterium species, similar to canonical MMR downregulation.

The alternative sigma factor σB may negatively regulate nucS expression during stationary phase.

Candidate compounds modulate nucS expression, showing responsiveness to environmental cues.

Abstract

Mismatch repair (MMR) system alterations can trigger transient hypermutation, promoting adaptive mutations under stress, such as antibiotic exposure. While most organisms use MutS and MutL protein families for MMR, many archaea and actinobacteria, including the major human pathogen Mycobacterium tuberculosis, lack these components and instead rely on NucS, a structurally distinct enzyme driving a non-canonical MMR pathway. Given the role of MMR in mutation control, understanding how nucS expression is regulated could be essential for uncovering the molecular basis of antibiotic resistance development in mycobacteria. In this study, we characterized the nucS promoter and transcription start site in Mycobacterium smegmatis. We found that nucS expression declines during the stationary phase in both M. smegmatis and M. tuberculosis, paralleling replication activity and canonical MMR downregulation. Our data suggest that the alternative sigma factor σB may negatively regulate nucS expression during this phase. Additionally, we identified candidate compounds that may modulate nucS expression, underscoring its responsiveness to environmental cues. These findings enhance our understanding of mycobacterial stress responses and lay the groundwork for exploring antibiotic resistance mechanisms. Strikingly, our work reveals a case of double convergent evolution: both canonical (MutS/MutL) and non-canonical (NucS) pathways have independently evolved not only the same DNA repair function, but also similar regulatory frameworks for genome integrity preservation under stress conditions.

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