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An additional proofreader contributes to DNA replication fidelity in mycobacteria.

Author information

Affiliations

  • 1. Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health, Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
      Authors
    • Deng MZ 1
    • Cui SJ 1, 6
    • Wang YX 1, 6
    • Fu H 1
    • Xu YY 1
    • Cai X 1
    • Lyu LD 1, 5
    (7 authors)
  • 2. Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
      Authors
    • Liu Q 2
    • Fortune SM 2
    (2 authors)
  • 3. Shanghai Zelixir Biotech Company Ltd., Shanghai 200030, China.
      Authors
    • Zhu G 3
    • Wang S 3
    (2 authors)
  • 4. Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China.
      Authors
    • Gan M 4
    (1 author)
  • 5. Shanghai Clinical Research Center for Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai 200433, China.
      Authors
    • Sha W 5
    • Lyu LD 1, 5
    (2 authors)
    • Show all (6)

ORCIDs linked to this article

Show all (7)

Proceedings of the National Academy of Sciences of the United States of America, 14 Aug 2024, 121(34):e2322938121
https://doi.org/10.1073/pnas.2322938121 PMID: 39141351 

Free full text available after 14 Feb 2025

Abstract 

The removal of mis-incorporated nucleotides by proofreading activity ensures DNA replication fidelity. Whereas the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli, it has been shown that proofreading in a majority of bacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase, despite the presence of a DnaQ homolog that is structurally and functionally distinct from E. coli DnaQ. However, the biological functions of this type of noncanonical DnaQ remain unclear. Here, we provide independent evidence that noncanonical DnaQ functions as an additional proofreader for mycobacteria. Using the mutation accumulation assay in combination with whole-genome sequencing, we showed that depletion of DnaQ in Mycolicibacterium smegmatis leads to an increased mutation rate, resulting in AT-biased mutagenesis and increased insertions/deletions in the homopolymer tract. Our results showed that mycobacterial DnaQ binds to the β clamp and functions synergistically with the PHP domain proofreader to correct replication errors. Furthermore, the loss of dnaQ results in replication fork dysfunction, leading to attenuated growth and increased mutagenesis on subinhibitory fluoroquinolones potentially due to increased vulnerability to fork collapse. By analyzing the sequence polymorphism of dnaQ in clinical isolates of Mycobacterium tuberculosis (Mtb), we demonstrated that a naturally evolved DnaQ variant prevalent in Mtb lineage 4.3 may enable hypermutability and is associated with drug resistance. These results establish a coproofreading model and suggest a division of labor between DnaQ and PHP domain proofreader. This study also provides real-world evidence that a mutator-driven evolutionary pathway may exist during the adaptation of Mtb.

Full text links 

Read article at publisher's site: https://doi.org/10.1073/pnas.2322938121

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Funding 

Funders who supported this work.

HHS | NIH (1)

MOST | National Key Research and Development Program of China (1)

MOST | National Key Research and Development Program of China (NKPs) (1)

MOST | National Natural Science Foundation of China (5)

MOST | National Natural Science Foundation of China (NSFC) (5)

NIAID NIH HHS (1)