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Research Article

Deep-sea vent phage DNA polymerase specifically initiates DNA synthesis in the absence of primers

Bin Zhu, Longfei Wang, Hitoshi Mitsunobu, Xueling Lu, Alfredo J. Hernandez, Yukari Yoshida-Takashima, Takuro Nunoura, Stanley Tabor, and Charles C. Richardson
PNAS March 21, 2017 114 (12) E2310-E2318; first published March 6, 2017; https://doi.org/10.1073/pnas.1700280114
Bin Zhu
aKey Laboratory of Molecular Biophysics, the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China;
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  • For correspondence: ccr@hms.harvard.edu Bin_Zhu@hust.edu.cn
Longfei Wang
bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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Hitoshi Mitsunobu
bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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Xueling Lu
aKey Laboratory of Molecular Biophysics, the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China;
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Alfredo J. Hernandez
bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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Yukari Yoshida-Takashima
cDepartment of Subsurface Geobiological Analysis and Research (D-SUGAR), Japan Agency for Marine-Earth Science and Technology (JAMSTEC), 2-15 Natsushima-cho, Yokosuka, Kanagawa 237-0061, Japan;
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Takuro Nunoura
dResearch and Development (R&D) Center for Marine Biosciences, Japan Agency for Marine-Earth Science and Technology (JAMSTEC), 2-15 Natsushima-cho, Yokosuka, Kanagawa 237-0061, Japan
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Stanley Tabor
bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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Charles C. Richardson
bDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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  • For correspondence: ccr@hms.harvard.edu Bin_Zhu@hust.edu.cn
  1. Contributed by Charles C. Richardson, February 2, 2017 (sent for review January 9, 2017; reviewed by Ulrich Hübscher and Margarita Salas)

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Significance

Most DNA polymerases initiate DNA synthesis by extending a preexisting primer. Exceptions to this dogma are recently characterized bifunctional primase–polymerases (prim–pols) that resemble archaeal primases in their structure and initiate DNA synthesis de novo using only NTPs or dNTPs. We report here a DNA polymerase encoded by a phage NrS-1 from deep-sea vents. NrS-1 has a genome organization unlike any other known phage. Although this polymerase does not contain a zinc-binding motif typical for primases, it is nonetheless able to initiate DNA synthesis from a specific DNA sequence exclusively using dNTPs. Thus, it represents a unique de novo replicative DNA polymerase that possesses features found in DNA polymerases, primases, and RNA polymerases.

Abstract

A DNA polymerase is encoded by the deep-sea vent phage NrS-1. NrS-1 has a unique genome organization containing genes that are predicted to encode a helicase and a single-stranded DNA (ssDNA)-binding protein. The gene for an unknown protein shares weak homology with the bifunctional primase–polymerases (prim–pols) from archaeal plasmids but is missing the zinc-binding domain typically found in primases. We show that this gene product has efficient DNA polymerase activity and is processive in DNA synthesis in the presence of the NrS-1 helicase and ssDNA-binding protein. Remarkably, this NrS-1 DNA polymerase initiates DNA synthesis from a specific template DNA sequence in the absence of any primer. The de novo DNA polymerase activity resides in the N-terminal domain of the protein, whereas the C-terminal domain enhances DNA binding.

  • NrS-1
  • primase
  • prim–pol
  • helicase
  • ssDNA-binding protein

Footnotes

  • ↵1To whom correspondence may be addressed. Email: ccr{at}hms.harvard.edu or Bin_Zhu{at}hust.edu.cn.
  • Author contributions: B.Z. and C.C.R. designed research; B.Z., L.W., H.M., and X.L. performed research; A.J.H., Y.Y.-T., and T.N. contributed new reagents/analytic tools; B.Z., S.T., and C.C.R. analyzed data; and B.Z., L.W., A.J.H., Y.Y.-T., T.N., S.T., and C.C.R. wrote the paper.

  • Reviewers: U.H., University of Zurich; and M.S., Consejo Superior de Investigaciones Científicas (CSIC).

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700280114/-/DCSupplemental.

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De novo DNA polymerase from deep-sea vent
Bin Zhu, Longfei Wang, Hitoshi Mitsunobu, Xueling Lu, Alfredo J. Hernandez, Yukari Yoshida-Takashima, Takuro Nunoura, Stanley Tabor, Charles C. Richardson
Proceedings of the National Academy of Sciences Mar 2017, 114 (12) E2310-E2318; DOI: 10.1073/pnas.1700280114

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De novo DNA polymerase from deep-sea vent
Bin Zhu, Longfei Wang, Hitoshi Mitsunobu, Xueling Lu, Alfredo J. Hernandez, Yukari Yoshida-Takashima, Takuro Nunoura, Stanley Tabor, Charles C. Richardson
Proceedings of the National Academy of Sciences Mar 2017, 114 (12) E2310-E2318; DOI: 10.1073/pnas.1700280114
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