DNA Repair and Mutagenesis in Mycobacteria

Mycobacterial DNA repair

The Glickman lab, in close collaboration with the Shuman lab, is broadly interested in the pathways and regulation of DNA repair in mycobacteria. Our goals in the DNA repair arena are twofold: 1) to understand the pathways and regulation of DNA repair in mycobacteria as a new model system for prokaryotic repair and 2) to use the knowledge gathered to understand the role of DNA repair pathways in resisting host inflicted DNA damage and the mutagenesis and antimicrobial resistance that results.

These studies have revealed multiple novel aspects of mycobacterial DNA and repair and mutagenesis that differ from more commonly studied model organisms. The include the presence and features of three pathways of double strand break repair (NHEJ, SSA, and HR), the role of phosphorylation in regulating RecA function, the role of the MutT system in antibiotic action, and pathways of mutagenesis mediated by translesion polymerases. 

Funded by NIH grant AI 064693
  1. Gong C., et al. Mechanism of nonhomologous end-joining in mycobacteria: a low-fidelity repair system driven by Ku, ligase D and ligase C. Nat Struct Mol Biol, 2005. 12(4): p. 304-12.
  2. Shuman S. and Glickman M.S. Bacterial DNA repair by non-homologous end joining. Nat Rev Microbiol, 2007. 5(11): p. 852-61.
  3. Aniukwu J., Glickman M.S., and Shuman S. The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends. Genes Dev, 2008. 22(4): p. 512-27.
  4. Sinha K.M., et al. AdnAB: a new DSB-resecting motor-nuclease from mycobacteria. Genes Dev, 2009. 23(12): p. 1423-37.
  5. Stallings CL, Stephanou NC, Chu L, Hochschild A, Nickels BE, Glickman MS. CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence. Cell. 2009 Jul 10;138(1):146-59. doi: 10.1016/j.cell.2009.04.041.
  6. Gupta R., et al. Mycobacteria exploit three genetically distinct DNA double-strand break repair pathways. Mol Microbiol, 2011. 79(2): p. 316-30.
  7. Heaton BE, Barkan D, Bongiorno P, Karakousis PC, Glickman MS. Deficiency of double-strand DNA break repair does not impair Mycobacterium tuberculosis virulence in multiple animal models of infection. Infect Immun. 2014 Aug;82(8):3177-85. doi: 10.1128/IAI.01540-14. PMID:24842925; PMCID: PMC4136208.
  8. Gupta R, Unciuleac MC, Shuman S, Glickman MS. Homologous recombination mediated by the mycobacterial AdnAB helicase without end resection by the AdnAB nucleases. Nucleic Acids Res. 2017 Jan 25;45(2):762-774. doi: 10.1093/nar/gkw1130. PMID:27899634; PMCID: PMC5314763.
  9. Wipperman MF, Heaton BE, Nautiyal A, Adefisayo O, Evans H, Gupta R, van Ditmarsch D, Soni R, Hendrickson R, Johnson J, Krogan N, Glickman MS. Mycobacterial mutagenesis and drug resistance are controlled by phosphorylation- and cardiolipin-mediated inhibition of the RecA coprotease. Mol Cell. 2018 Aug 22. doi: 10.1016/j.molcel.2018.07.037.
  10. Dupuy P, Howlader M, Glickman MS. A multilayered repair system protects the mycobacterial chromosome from endogenous and antibiotic-induced oxidative damage. Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19517-19527. doi: 10.1073/pnas.2006792117. PMID:32727901; PMCID: PMC7431094.
  11. Adefisayo OO, Dupuy P, Nautiyal A, Bean JM, Glickman MS. Division of labor between SOS and PafBC in mycobacterial DNA repair and mutagenesis. Nucleic Acids Res. 2021 Dec 16;49(22):12805-12819. doi: 10.1093/nar/gkab1169. PMID:34871411; PMCID: PMC8682763.
  12. Dupuy P, Ghosh S, Adefisayo O, Buglino J, Shuman S, Glickman MS. Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis. Nat Commun. 2022 Aug 2;13(1):4493. doi: 10.1038/s41467-022-32022-8. PMID:35918328; PMCID: PMC9346131.
  13. Dupuy P, Ghosh S, Fay A, Adefisayo O, Gupta R, Shuman S, Glickman MS. Roles for mycobacterial DinB2 in frameshift and substitution mutagenesis. eLife. 2023 May 4;12:e83094. doi: 10.7554/eLife.83094. PMID:37141254; PMCID: PMC10159617.

Project Members

M. Maria Elgrail
Allison Fay