Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome

Andrey G. Baranovskiy, Nigar D. Babayeva, Yinbo Zhang, Jianyou Gu, Yoshiaki Suwa, Youri I Pavlov, Tahir H Tahirov

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The human primosome, a 340-kilodalton complex of primase and DNA polymeraseα(Polo α), synthesizes chimeric RNA-DNA primers to be extended by replicative DNA polymerases δand ϵ. The intricate mechanism of concerted primer synthesis by two catalytic centers was an enigma for over three decades. Here we report the crystal structures of two key complexes, the human primosome and the C-terminal domain of the primase large subunit (p58C ) with bound DNA/RNA duplex. These structures, along with analysis of primase/polymerase activities, provide a plausible mechanism for all transactions of the primosome including initiation, elongation, accurate counting of RNA primer length, primer transfer to Polα, and concerted autoregulation of alternate activation/inhibition of the catalytic centers. Our findings reveal a central role of p58C in the coordinated actions of two catalytic domains in the primosome and ultimately could impact the design of anticancer drugs.

Original languageEnglish (US)
Pages (from-to)10006-10020
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Issue number19
DOIs
StatePublished - May 6 2016

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DNA Primase
DNA Primers
DNA-Directed DNA Polymerase
RNA
Elongation
Crystal structure
Drug Design
Chemical activation
DNA
Catalytic Domain
Homeostasis
Pharmaceutical Preparations
RNA primers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome. / Baranovskiy, Andrey G.; Babayeva, Nigar D.; Zhang, Yinbo; Gu, Jianyou; Suwa, Yoshiaki; Pavlov, Youri I; Tahirov, Tahir H.

In: Journal of Biological Chemistry, Vol. 291, No. 19, 06.05.2016, p. 10006-10020.

Research output: Contribution to journalArticle

Baranovskiy, Andrey G. ; Babayeva, Nigar D. ; Zhang, Yinbo ; Gu, Jianyou ; Suwa, Yoshiaki ; Pavlov, Youri I ; Tahirov, Tahir H. / Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 19. pp. 10006-10020.
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