{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:27:20Z","timestamp":1790123240692,"version":"4.0.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI 064693"],"award-info":[{"award-number":["AI 064693"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>DNA repair systems allow microbes to survive in diverse environments that compromise chromosomal integrity. Pathogens such as Mycobacterium\u00a0tuberculosis must contend with the genotoxic host environment, which generates the mutations that underlie antibiotic resistance. Mycobacteria encode the widely distributed SOS pathway, governed by the LexA repressor, but also encode PafBC, a positive regulator of the transcriptional DNA damage response (DDR). Although the transcriptional outputs of these systems have been characterized, their full functional division of labor in survival and mutagenesis is unknown. Here, we specifically ablate the PafBC or SOS pathways, alone and in combination, and test their relative contributions to repair. We find that SOS and PafBC have both distinct and overlapping roles that depend on the type of DNA damage. Most notably, we find that quinolone antibiotics and replication fork perturbation are inducers of the PafBC pathway, and that chromosomal mutagenesis is codependent on PafBC and SOS, through shared regulation of the DnaE2\/ImuA\/B mutasome. These studies define the complex transcriptional regulatory network of the DDR in mycobacteria and provide new insight into the regulatory mechanisms controlling the genesis of antibiotic resistance in M. tuberculosis.<\/jats:p>","DOI":"10.1093\/nar\/gkab1169","type":"journal-article","created":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T16:05:59Z","timestamp":1636560359000},"page":"12805-12819","source":"Crossref","is-referenced-by-count":37,"title":["Division of labor between SOS and PafBC in mycobacterial DNA repair and mutagenesis"],"prefix":"10.1093","volume":"49","author":[{"given":"Oyindamola O","family":"Adefisayo","sequence":"first","affiliation":[{"name":"Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School,\u00a01300 York Avenue,\u00a0New York, NY 10065, USA"},{"name":"Immunology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Dupuy","sequence":"additional","affiliation":[{"name":"Immunology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astha","family":"Nautiyal","sequence":"additional","affiliation":[{"name":"Immunology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M","family":"Bean","sequence":"additional","affiliation":[{"name":"Immunology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7918-5164","authenticated-orcid":false,"given":"Michael\u00a0S","family":"Glickman","sequence":"additional","affiliation":[{"name":"Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School,\u00a01300 York Avenue,\u00a0New York, NY 10065, USA"},{"name":"Immunology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10025, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"2021121718023082100_B1","doi-asserted-by":"crossref","first-page":"8841","DOI":"10.1073\/pnas.97.16.8841","article-title":"Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens","volume":"97","author":"Nathan","year":"2000","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021121718023082100_B2","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1128\/CMR.00060-05","article-title":"Tuberculosis chemotherapy: the influence of bacillary stress and damage response pathways on drug efficacy","volume":"19","author":"Warner","year":"2006","journal-title":"Clin. Microbiol. Rev."},{"key":"2021121718023082100_B3","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1128\/IAI.73.8.4581-4587.2005","article-title":"Role for nucleotide excision repair in virulence of Mycobacterium tuberculosis","volume":"73","author":"Darwin","year":"2005","journal-title":"Infect. Immun."},{"key":"2021121718023082100_B4","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1128\/JB.06654-11","article-title":"Important role for Mycobacterium tuberculosis UvrD1 in pathogenesis and persistence apart from its function in nucleotide excision repair","volume":"194","author":"Houghton","year":"2012","journal-title":"J. Bacteriol."},{"key":"2021121718023082100_B5","doi-asserted-by":"crossref","first-page":"e1009452","DOI":"10.1371\/journal.ppat.1009452","article-title":"Compromised base excision repair pathway in Mycobacterium tuberculosis imparts superior adaptability in the host","volume":"17","author":"Naz","year":"2021","journal-title":"PLoS Pathog."},{"key":"2021121718023082100_B6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/j.1574-6976.2009.00170.x","article-title":"DNA repair in Mycobacterium tuberculosis revisited","volume":"33","author":"Dos\u00a0Vultos","year":"2009","journal-title":"FEMS Microbiol. Rev."},{"key":"2021121718023082100_B7","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1006\/jmbi.1993.1254","article-title":"The LexA repressor binds within the deep helical groove of the activated RecA filament","volume":"231","author":"Yu","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2021121718023082100_B8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.molcel.2018.07.037","article-title":"Mycobacterial mutagenesis and drug resistance are controlled by phosphorylation- and cardiolipin-mediated inhibition of the RecA coprotease","volume":"72","author":"Wipperman","year":"2018","journal-title":"Mol. Cell"},{"key":"2021121718023082100_B9","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1093\/jac\/dku080","article-title":"Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery","volume":"69","author":"Nautiyal","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"2021121718023082100_B10","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1016\/j.celrep.2018.05.073","article-title":"The mycobacterial LexA\/RecA-independent DNA damage response is controlled by PafBC and the Pup-proteasome system","volume":"23","author":"M\u00fcller","year":"2018","journal-title":"Cell Rep."},{"key":"2021121718023082100_B11","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.1128\/JB.01597-06","article-title":"Characterization of the proteasome accessory factor (paf) operon in Mycobacterium tuberculosis","volume":"189","author":"Festa","year":"2007","journal-title":"J. Bacteriol."},{"key":"2021121718023082100_B12","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1046\/j.1365-2958.2003.03765.x","article-title":"The majority of inducible DNA repair genes in Mycobacterium tuberculosis are induced independently of RecA","volume":"50","author":"Rand","year":"2003","journal-title":"Mol. Microbiol."},{"key":"2021121718023082100_B13","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.3390\/cells10051168","article-title":"Dissecting the RecA-(in)dependent response to mitomycin C in Mycobacterium tuberculosis using transcriptional profiling and proteomics analyses","volume":"10","author":"Brzostek","year":"2021","journal-title":"Cells"},{"key":"2021121718023082100_B14","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.3389\/fmicb.2020.01785","article-title":"The DNA damage inducible SOS response is a key player in the generation of bacterial persister cells and population wide tolerance","volume":"11","author":"Podlesek","year":"2020","journal-title":"Front. Microbiol."},{"key":"2021121718023082100_B15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0092-8674(03)00270-8","article-title":"DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis","volume":"113","author":"Boshoff","year":"2003","journal-title":"Cell"},{"key":"2021121718023082100_B16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/10409230701260258","article-title":"Regulation of bacterial RecA protein function","volume":"42","author":"Cox","year":"2007","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"2021121718023082100_B17","doi-asserted-by":"crossref","first-page":"6005","DOI":"10.1128\/JB.185.20.6005-6015.2003","article-title":"Characterization of the two Mycobacterium tuberculosis recA promoters","volume":"185","author":"Gopaul","year":"2003","journal-title":"J. Bacteriol."},{"key":"2021121718023082100_B18","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1111\/j.1365-2958.2010.07463.x","article-title":"Mycobacteria exploit three genetically distinct DNA double-strand break repair pathways","volume":"79","author":"Gupta","year":"2011","journal-title":"Mol. Microbiol."},{"key":"2021121718023082100_B19","doi-asserted-by":"crossref","first-page":"e00013-18","DOI":"10.1128\/MMBR.00013-18","article-title":"Replication fork breakage and restart in Escherichia coli","volume":"82","author":"Michel","year":"2018","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"2021121718023082100_B20","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.gene.2010.09.005","article-title":"An improved counterselectable marker system for mycobacterial recombination using galK and 2-deoxy-galactose","volume":"470","author":"Barkan","year":"2011","journal-title":"Gene"},{"key":"2021121718023082100_B21","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/nar\/gkw1130","article-title":"Homologous recombination mediated by the mycobacterial AdnAB helicase without end resection by the AdnAB nucleases","volume":"45","author":"Gupta","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2021121718023082100_B22","doi-asserted-by":"crossref","first-page":"e00010-20","DOI":"10.1128\/mBio.00010-20","article-title":"A simple, cost-effective, and robust method for rRNA depletion in RNA-sequencing studies","volume":"11","author":"Culviner","year":"2020","journal-title":"mBio"},{"key":"2021121718023082100_B23","doi-asserted-by":"crossref","first-page":"e22520","DOI":"10.7554\/eLife.22520","article-title":"Structure and function of the mycobacterial transcription initiation complex with the essential regulator RbpA","volume":"6","author":"Hubin","year":"2017","journal-title":"eLife"},{"key":"2021121718023082100_B24","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.tibs.2016.05.006","article-title":"RecA: regulation and mechanism of a molecular search engine (Trends in Biochemical Sciences, June 2016, Vol. 41, No. 6, 491\u2013507)","volume":"41","author":"Bell","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"2021121718023082100_B25","doi-asserted-by":"crossref","first-page":"3987","DOI":"10.1073\/pnas.84.12.3987","article-title":"Lysine-156 and serine-119 are required for LexA repressor cleavage: a possible mechanism","volume":"84","author":"Slilaty","year":"1987","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021121718023082100_B26","doi-asserted-by":"crossref","first-page":"13093","DOI":"10.1073\/pnas.1002614107","article-title":"Essential roles for imuA\u2032- and imuB-encoded accessory factors in DnaE2-dependent mutagenesis in Mycobacterium tuberculosis","volume":"107","author":"Warner","year":"2010","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021121718023082100_B27","first-page":"57","article-title":"Identification of a promoter motif regulating the major DNA damage response mechanism of Mycobacterium tuberculosis","volume":"238","author":"Gamulin","year":"2004","journal-title":"FEMS Microbiol. Lett."},{"key":"2021121718023082100_B28","doi-asserted-by":"crossref","first-page":"4653","DOI":"10.1038\/s41467-019-12567-x","article-title":"Structure and functional implications of WYL domain-containing bacterial DNA damage response regulator PafBC","volume":"10","author":"M\u00fcller","year":"2019","journal-title":"Nat. Commun."},{"key":"2021121718023082100_B29","doi-asserted-by":"crossref","first-page":"2572","DOI":"10.1021\/cb500573z","article-title":"Novel imidazoline antimicrobial scaffold that inhibits DNA replication with activity against mycobacteria and drug resistant Gram-positive cocci","volume":"9","author":"Harris","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"2021121718023082100_B30","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/jac\/48.4.479","article-title":"Effect of different classes of inhibitors on DNA gyrase from Mycobacterium smegmatis","volume":"48","author":"Chatterji","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"2021121718023082100_B31","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1128\/JB.01135-09","article-title":"Role of the DinB homologs Rv1537 and Rv3056 in Mycobacterium tuberculosis","volume":"192","author":"Kana","year":"2010","journal-title":"J. Bacteriol."},{"key":"2021121718023082100_B32","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1056\/NEJMoa2033400","article-title":"Four-month rifapentine regimens with or without moxifloxacin for tuberculosis","volume":"384","author":"Dorman","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"2021121718023082100_B33","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1093\/jac\/dkq496","article-title":"Effect of recA inactivation on mutagenesis of Escherichia coli exposed to sublethal concentrations of antimicrobials","volume":"66","author":"Thi","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"2021121718023082100_B34","doi-asserted-by":"crossref","first-page":"fuaa071","DOI":"10.1093\/femsre\/fuaa071","article-title":"The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis","volume":"45","author":"Castro","year":"2021","journal-title":"FEMS Microbiol. Rev."},{"key":"2021121718023082100_B35","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1093\/jac\/dki191","article-title":"Effect of subinhibitory concentrations of ciprofloxacin on Mycobacterium fortuitum mutation rates","volume":"56","author":"Gillespie","year":"2005","journal-title":"J. Antimicrob. Chemother."},{"key":"2021121718023082100_B36","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1128\/JB.01066-09","article-title":"RecA-independent DNA damage induction of Mycobacterium tuberculosis ruvC despite an appropriately located SOS box","volume":"192","author":"Dawson","year":"2010","journal-title":"J. Bacteriol."},{"key":"2021121718023082100_B37","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1046\/j.1365-2958.2002.03199.x","article-title":"DNA damage induction of recA in Mycobacterium tuberculosis independently of RecA and LexA","volume":"46","author":"Davis","year":"2002","journal-title":"Mol. Microbiol."}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/49\/22\/12805\/41810743\/gkab1169.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/49\/22\/12805\/41810743\/gkab1169.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T14:31:58Z","timestamp":1639751518000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/49\/22\/12805\/6454275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,12,6]]},"published-print":{"date-parts":[[2021,12,16]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkab1169","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.05.455301","asserted-by":"object"}]},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,16]]},"published":{"date-parts":[[2021,12,6]]}}}