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Title: The roles of selected Mycobacterium tuberculosis genes in DNA repair and pathogenesis
Author: Curtis, R. L.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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The bacterium which causes tuberculosis, is able to survive and replicate inside the hostile environment of the macrophage. Amongst other survival strategies. Mtb possesses mechanisms tor repairing DNA damaged bv exposure to reactive oxvgen and nitrogen species produced bv activated macrophages. Multiple DNA repair pathwavs exist and a number of genes of unknown function are induced under conditions of DNA damage. In this studv. the roles of previously uneharaeterised genes predicted to be involved in the repair ot damaged DNA. or induced bv DNA damage, have been investigated by targeted mutation in Mtb. The genes under studv are Rv() o7c and Rv() oX. homologous to Ku and A I P-dependent DNA ligase components of the non-homologous end joining system in eukaryotes. Rv21 T. which shows a high level of homology to ("ho. a recently discovered component of nucleotide excision repair in / E.coli. and Rv33 oc. which has been shown to be DNA damage inducible. Mutant strains of Mtb were constructed with deletions in each ot these genes, as well as a strain lacking both Rv() o7c and Rv() oX. I hese mutant strains were characterised in comparison with the wild type strain // vitro, following exposure to a variety ot DNA damaging agents. The results revealed different patterns of heightened sensitivities when individual repair pathways were affected. Preliminary screens suggested a role in survival following exposure to oxidative damage for Rv211 in vitro and further investigation confirmed this. This result supports previous work implicating nucleotide excision repair for this type of damage in Mtb. The ability of the strains to grow and surv ive in a mouse model of infection was assessed. 1 he mutants deficient in components of the non-homologous end joining system were found to display attenuated growth in activated macrophages and possibly at late stages of infection in mice. This may suggest a potential role for non-homologous end joining during infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available