# Mycobacterial DNA repair and mutagenesis

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $663,906

## Abstract

Mycobacteria are a genus of the phylum Actinobacteria that includes the human pathogens M.
tuberculosis and M. leprae and their avirulent relative M. smegmatis. Human infections with M.
tuberculosis (the agent of tuberculosis) and M. leprae (agent of leprosy) cause substantial human
suffering. Tuberculosis accounts for ~2 million deaths annually. M. tuberculosis is increasingly
antibiotic resistant, solely through the acquisition of mutations in chromosomal genes. The
importance of mutagenesis in the evolution of M. tuberculosis antimicrobial resistance, and the
related importance of DNA repair pathways in resisting host-inflicted DNA damage, prompts our
interest in the mechanisms by which mycobacteria respond to and repair DNA damage. In
addition to this important relevance to human health, mycobacteria have emerged as fertile model
system to study prokaryotic DNA repair, due to the complexity of the pathways involved and the
novel mechanisms that govern these pathways. Our long range goals in this project are to
elucidate the DNA repair mechanisms of Mycobacteria. Our work supported by this award has
shown that mycobacterial DNA repair differs from the classic E. coli model system with respect to
the number of pathway options for the repair of DNA double-strand breaks (DSBs), the roster of
DNA repair enzymes, and the regulation of the DNA damage response (DDR). Our premise is
that understanding the distinctive features of mycobacterial DNA repair will illuminate the
evolution and diversification of repair strategies and suggest new approaches to combat
mycobacterial infection and emergence of antibiotic resistance. Our agenda for the next phase of
the project focuses on three themes in mycobacterial DNA repair: (i) the mechanism of DSB
resection during homologous recombination (HR) by the AdnAB helicase-nuclease; (ii) the role of
RecA phosphorylation and RecA interaction with membrane phospholipids in controlling the DNA
damage response; and (iii) the structure and repair activities of the DNA helicase Lhr. We propose
a combined approach that leverages integrated biochemical, structural, and genetic approaches
to understand these DNA repair systems of mycobacteria. Through these studies we will elucidate
new mechanisms of DNA repair in mycobacteria, discoveries that will both advance basic
knowledge of prokaryotic DNA repair and elucidate pathways relevant to M. tuberculosis drug
resistance and pathogenesis.

## Key facts

- **NIH application ID:** 10162479
- **Project number:** 5R01AI064693-16
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Michael S Glickman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $663,906
- **Award type:** 5
- **Project period:** 2005-02-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162479

## Citation

> US National Institutes of Health, RePORTER application 10162479, Mycobacterial DNA repair and mutagenesis (5R01AI064693-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10162479. Licensed CC0.

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