부산대학교 도서관

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 [beta] subunit ([beta] clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuB.sup.AAAAGG mutant containing a disrupted [beta] clamp-binding motif abolishes ImuB--[beta] clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this [beta] clamp-binding antibiotic collapses pre-formed ImuB--[beta] clamp complexes. These observations establish the essentiality of the ImuB--[beta] 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.
Byline: Sophia Gessner, Zela Alexandria-Mae Martin, Michael A Reiche, Joana A Santos, Ryan Dinkele, Atondaho Ramudzuli, Neeraj Dhar, Timothy J de Wet, Saber Anoosheh, Dirk M Lang, Jesse Aaron, Teng-Leong [...]