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.

doi:10.1074/jbc.M116.717405

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

Journal Article · Sun May 01 00:00:00 EDT 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M116.717405· OSTI ID:1769433

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

The human primosome, a 340-kilodalton complex of primase and DNA polymerase α (Polα), synthesizes chimeric RNA-DNA primers to be extended by replicative DNA polymerases δ and 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 (p58_C) 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. Furthermore, our findings reveal a central role of p58_C in the coordinated actions of two catalytic domains in the primosome and ultimately could impact the design of anticancer drugs.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health

Grant/Contract Number:: AC02–06CH11357; GM101167; P30CA036727; P41 GM103403; S10 RR029205

OSTI ID:: 1769433

Alternate ID(s):: OSTI ID: 1253791

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Vol. 291 Journal Issue: 19; ISSN 0021-9258

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 71 works

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

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