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Nat Genet. 2015 Jun;47(6):677-81. doi: 10.1038/ng.3269. Epub 2015 Apr 20.

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

Author information

1
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
2
Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, UK.
3
1] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
1] Swiss Tropical and Public Health Institute, Basel, Switzerland. [2] University of Basel, Basel, Switzerland.
5
1] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Ragon Institute of Massachusetts General Hospital, Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

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.

PMID:
25894501
PMCID:
PMC4449270
DOI:
10.1038/ng.3269
[Indexed for MEDLINE]
Free PMC Article

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