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J. Bacteriol. doi:10.1128/JB.01409-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Function and regulation of class I ribonucleotide reductase-encoding genes in mycobacteria

MRC/NHLS/WITS Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, School of Pathology, University of the Witwatersrand and the National Health Laboratory Service, Johannesburg 2000, South Africa; Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute, International Center for Public Health, 225 Warren St., Newark, NJ 07103-3535, USA

^* To whom correspondence should be addressed. Email: bavesh.kana{at}nhls.ac.za. valerie.mizrahi{at}wits.ac.za.

	Abstract

Ribonucleotide reductases (RNRs) are crucial to all living cells since they provide deoxyribonucleotides (dNTPs) for DNA synthesis and repair. In Mycobacterium tuberculosis, a class Ib RNR comprising nrdE- and nrdF2-encoded subunits is essential for growth in vitro. Interestingly, the genome of this obligate human pathogen also contains nrdF1 (Rv1981c) and nrdB (Rv0233) genes encoding an alternate class Ib RNR small (R2) subunit and a putative class Ic RNR R2 subunit, respectively. However, the role(s) of these subunits in dNTP provision during M. tuberculosis pathogenesis is unknown. In this study, we demonstrate that nrdF1 and nrdB are dispensable for growth and survival of M. tuberculosis after exposure to various stresses in vitro and, further, that neither gene is required for growth and survival in mice. These observations argue against a specialist role for the alternate R2 subunits under the conditions tested. Through the construction of nrdR-deficient mutants of M. tuberculosis and M. smegmatis, we establish that the genes encoding the essential class Ib RNR subunits are specifically regulated by an NrdR-type repressor. Moreover, a strain of M. smegmatis mc²155 lacking the 56-kb chromosomal region that includes duplicates of nrdHIE and nrdF2, and a mutant retaining only one copy of nrdF2, are shown to be hypersensitive to the class I RNR inhibitor, hydroxyurea, as a result of depleted levels of the target. Together, our observations identify a potential vulnerability in dNTP provision in mycobacteria, and thereby offer a compelling rationale for pursuing the class Ib RNR as a target for drug discovery.