Mycobacterial DnaQ is an Alternative Proofreader Ensuring DNA Replication Fidelity.

Autor:	Deng MZ; Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health (MOE/NHC), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China.; These authors contributed equally., Liu Q; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.; These authors contributed equally., Cui SJ; Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health (MOE/NHC), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China.; Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, P.R.China., Fu H; Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health (MOE/NHC), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China.; CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences (CAS), Shanghai 200032, P.R.China.; University of Chinese Academy of Sciences, Beijing 100049, P.R.China., Gan M; Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, 201102, P.R.China., Xu YY; Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health (MOE/NHC), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China., Cai X; Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health (MOE/NHC), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China., Sha W; Shanghai Clinical Research Center for Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai 200433, P.R.China., Zhao GP; Department of Microbiology and Microbial Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, P.R.China.; CAS Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences (CAS), Shanghai 200032, P.R.China.; University of Chinese Academy of Sciences, Beijing 100049, P.R.China., Fortune SM; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115., Lyu LD; Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health (MOE/NHC), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R.China.; Shanghai Clinical Research Center for Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Shanghai 200433, P.R.China.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 26. Date of Electronic Publication: 2023 Oct 26.
DOI:	10.1101/2023.10.24.563508
Abstrakt:	Remove of mis-incorporated nucleotides ensures replicative fidelity. Although the ε-exonuclease DnaQ is a well-established proofreader in the model organism Escherichia coli , proofreading in mycobacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase despite the presence of an alternative DnaQ homolog. Here, we show that depletion of DnaQ in Mycolicibacterium smegmatis results in increased mutation rate, leading to AT-biased mutagenesis and elevated insertions/deletions in homopolymer tract. We demonstrated that mycobacterial DnaQ binds to the b-clamp and functions synergistically with the PHP domain to correct replication errors. Further, we found that the mycobacterial DnaQ sustains replicative fidelity upon chromosome topological stress. Intriguingly, we showed that a naturally evolved DnaQ variant prevalent in clinical Mycobacterium tuberculosis isolates enables hypermutability and is associated with extensive drug resistance. These results collectively establish that the alternative DnaQ functions in proofreading, and thus reveal that mycobacteria deploy two proofreaders to maintain replicative fidelity. Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Databáze:	MEDLINE
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