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J. Biol. Chem., Vol. 279, Issue 20, 20594-20606, May 14, 2004
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Biochemical and Genetic Analysis of the Four DNA Ligases of Mycobacteria*
From the Molecular Biology and Immunology Programs, Sloan-Kettering Institute, and Infectious Disease Division, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
Mycobacterium tuberculosis encodes an NAD+-dependent DNA ligase (LigA) plus three distinct ATP-dependent ligase homologs (LigB, LigC, and LigD). Here we purify and characterize the multiple DNA ligase enzymes of mycobacteria and probe genetically whether the ATP-dependent ligases are required for growth of M. tuberculosis. We find significant differences in the reactivity of mycobacterial ligases with a nicked DNA substrate, whereby LigA and LigB display vigorous nick sealing activity in the presence of NAD+ and ATP, respectively, whereas LigC and LigD, which have ATP-specific adenylyltransferase activity, display weak nick joining activity and generate high levels of the DNA-adenylate intermediate. All four of the mycobacterial ligases are monomeric enzymes. LigA has a low Km for NAD+ (1 µM) and is sensitive to a recently described pyridochromanone inhibitor of NAD+-dependent ligases. LigA is able to sustain growth of Saccharomyces cerevisiae in lieu of the essential yeast ligase Cdc9, but LigB, LigC, and LigD are not. LigB is distinguished by its relatively high Km for ATP (0.34 mM) and its dependence on a distinctive N-terminal domain for nick joining. None of the three ATP-dependent ligases are essential for mycobacterial growth. M. tuberculosis ligD
cells are defective in nonhomologous DNA end joining.
Received for publication, February 19, 2004
* 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.
To whom correspondence may be addressed. E-mail: glickmam{at}MSKCC.ORG. 
To whom correspondence may be addressed. E-mail: s-shuman{at}ski.mskcc.org.
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