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J. Biol. Chem., Vol. 278, Issue 27, 24350-24358, July 4, 2003

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Importance of Uracil DNA Glycosylase in Pseudomonas aeruginosa and Mycobacterium smegmatis, G+C-rich Bacteria, in Mutation Prevention, Tolerance to Acidified Nitrite, and Endurance in Mouse Macrophages^*

Jeganathan Venkatesh , Pradeep Kumar , Pulukuri Sai Murali Krishna, Ramanathapuram Manjunath  and Umesh Varshney ¶

From the Departments of Microbiology and Cell Biology and Biochemistry, Indian Institute of Science, Bangalore, 560 012 India

Uracil DNA glycosylase (Ung (or UDG)) initiates the excision repair of an unusual base, uracil, in DNA. Ung is a highly conserved protein found in all organisms. Paradoxically, loss of this evolutionarily conserved enzyme has not been seen to result in severe growth phenotypes in the cellular life forms. In this study, we chose G+C-rich genome containing bacteria (Pseudomonas aeruginosa and Mycobacterium smegmatis) as model organisms to investigate the biological significance of ung. Ung deficiency was created either by expression of a highly specific inhibitor protein, Ugi, and/or by targeted disruption of the ung gene. We show that abrogation of Ung activity in P. aeruginosa and M. smegmatis confers upon them an increased mutator phenotype and sensitivity to reactive nitrogen intermediates generated by acidified nitrite. Also, in a mouse macrophage infection model, P. aeruginosa (Ung^–) shows a significant decrease in its survival. Infections of the macrophages with M. smegmatis show an initial increase in the bacterial counts that remain for up to 48 h before a decline. Interestingly, abrogation of Ung activity in M. smegmatis results in nearly a total abolition of their multiplication and a much-decreased residency in macrophages stimulated with interferon . These observations suggest Ung as a useful target to control growth of G+C-rich bacteria.

Received for publication, February 28, 2003 , and in revised form, April 3, 2003.

^* This work was supported by research grants from Council of Scientific and Industrial Research, Department of Biotechnology, and Indian Council of Medical Research, New Delhi, India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Joint first authors.

^¶ To whom correspondence should be addressed: Dept. of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, 560 012, India. Tel.: 91-80-293-2686; Fax: 91-80-360-2697; 91-80-360-0683; E-mail: varshney{at}mcbl.iisc.ernet.in.

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