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DNA replication fidelity in Mycobacterium tuberculosis is mediated by an ancestral prokaryotic proofreader

Rock, Jeremy M. and Lang, Ulla F. and Chase, Michael R. and Ford, Christopher B. and Gerrick, Elias R. and Gawande, Richa and Coscolla, Mireia and Gagneux, Sebastien and Fortune, Sarah M. and Lamers, Meindert H.. (2015) DNA replication fidelity in Mycobacterium tuberculosis is mediated by an ancestral prokaryotic proofreader. Nature genetics, Vol. 47, H. 6. pp. 677-681.

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Official URL: http://edoc.unibas.ch/dok/A6391007

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Abstract

The DNA replication machinery is an important target for antibiotic development in increasingly drug-resistant bacteria, including Mycobacterium tuberculosis. Although blocking DNA replication leads to cell death, disrupting the processes used to ensure replication fidelity can accelerate mutation and the evolution of drug resistance. In Escherichia coli, the proofreading subunit of the replisome, the ɛ exonuclease, is essential for high-fidelity DNA replication; however, we find that the corresponding subunit is completely dispensable in M. tuberculosis. Rather, the mycobacterial replicative polymerase DnaE1 itself encodes an editing function that proofreads DNA replication, mediated by an intrinsic 3'-5' exonuclease activity within its PHP domain. Inactivation of the DnaE1 PHP domain increases the mutation rate by more than 3,000-fold. Moreover, phylogenetic analysis of DNA replication proofreading in the bacterial kingdom suggests that E. coli is a phylogenetic outlier and that PHP domain-mediated proofreading is widely conserved and indeed may be the ancestral prokaryotic proofreader.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Tuberculosis Research (Gagneux)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
UniBasel Contributors:Gagneux, Sebastien
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Nature Publ
ISSN:1061-4036
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Jul 2015 08:53
Deposited On:03 Jul 2015 08:53

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