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

Details

• Alternative Title:
  Nat Genet
• Personal Author:
  Rock, Jeremy M. ; Lang, Ulla F. ; Chase, Michael R. ; Ford, Christopher B. ; Gerrick, Elias R. ; Gawande, Richa ; Coscolla, Mireia ; Gagneux, Sebastien ; Fortune, Sarah M. ; Lamers, Meindert H.
• Description:
  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.
• Subjects:
  Amino Acid Sequence Antitubercular Agents Bacterial Proteins DNA, Bacterial DNA Polymerase III DNA Replication Drug Resistance, Bacterial Microbial Sensitivity Tests Molecular Sequence Data Mycobacterium Tuberculosis Phenotype Phylogeny Polymorphism, Single Nucleotide

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• Source:
  Nat Genet. 47(6):677-681
• Pubmed ID:
  25894501
• Pubmed Central ID:
  PMC4449270
• Document Type:
  Journal Article
• Funding:
  AI109755-01/AI/NIAID NIH HHSUnited States/ ; 1DP20D001378/DP/NCCDPHP CDC HHSUnited States/ ; U19AI076217/AI/NIAID NIH HHSUnited States/ ; P41 RR001209/RR/NCRR NIH HHSUnited States/ ; MC_U105197143/MRC_/Medical Research CouncilUnited Kingdom/ ; U19 AI076217/AI/NIAID NIH HHSUnited States/ ; U19 AI109755/AI/NIAID NIH HHSUnited States/
• Volume:
  47
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:ba9c679c51169c3616b4b07e25a2f1464ef51f787ed37ff716390f80a83cd1d7
• Download URL:
  https://stacks.cdc.gov/view/cdc/32538/cdc_32538_DS1.pdf
• File Type:
  [PDF - 601.77 KB ]