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U.S.A."],"published-print":{"date-parts":[[2026,6,30]]},"abstract":"<jats:p>\n                    Upon activation, macrophages generate substantial levels of reactive nitrogen species, which can induce alkylating damage in the DNA of intracellular\n                    <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                    ) and thereby restrict bacterial replication. However, the molecular mechanisms by which\n                    <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                    repairs such DNA lesions remain poorly understood. Here, we identified genes required for\n                    <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                    survival in distinct macrophage subsets using transposon insertion sequencing. Among these,\n                    <jats:italic toggle=\"yes\">tagA<\/jats:italic>\n                    displayed a specialized role in\n                    <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                    survival in M1-polarized macrophages, as well as in mice at 4 wk postinfection, a stage when macrophages are biased toward an M1-polarized state. Mechanistically, TagA conferred resistance to the DNA alkylating agent methyl methanesulfonate through its 3-methyladenine (3-MA) excision activity with Glu48 serving as a key catalytic residue for substrate binding. Critically, TagA was found to protect the\n                    <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                    genome from alkylation damage caused by nitrosative stress\u2014a hallmark of the M1-polarized macrophage microenvironment. Furthermore, pharmacological inhibition of inducible nitric oxide synthase (iNOS) with S-methylisothiourea sulfate in mice or genetic deletion of\n                    <jats:italic toggle=\"yes\">nos2a<\/jats:italic>\n                    in zebrafish markedly rescued the survival defect of \u0394\n                    <jats:italic toggle=\"yes\">tagA<\/jats:italic>\n                    . Together, these findings reveal a previously unappreciated mechanism by which the DNA repair enzyme TagA protects\n                    <jats:italic toggle=\"yes\">Mtb<\/jats:italic>\n                    against 3-MA DNA damage under nitrosative stress, thereby promoting bacterial survival in M1-polarized macrophages and during in vivo infection.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2613344123","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:06:47Z","timestamp":1782238007000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["A guardian role of TagA in protecting\n                    <i>Mycobacterium tuberculosis<\/i>\n                    from nitrosative 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