Activity and fidelity of human DNA polymerase α depend on primer structure

Baranovskiy, Andrey G.; Duong, Vincent N.; Babayeva, Nigar D.; Zhang, Yinbo; Pavlov, Youri I.; Anderson, Karen S.; Tahirov, Tahir H.

doi:10.1074/jbc.RA117.001074

Title: Activity and fidelity of human DNA polymerase α depend on primer structure

Journal Article · Tue May 01 00:00:00 EDT 2018 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.RA117.001074· OSTI ID:1769427

Baranovskiy, Andrey G.; Duong, Vincent N.; Babayeva, Nigar D.; Zhang, Yinbo; Pavlov, Youri I.; Anderson, Karen S.; Tahirov, Tahir H.

DNA polymerase α (Polα) plays an important role in genome replication. In a complex with primase, Polα synthesizes chimeric RNA–DNA primers necessary for replication of both chromosomal DNA strands. During RNA primer extension with deoxyribonucleotides, Polα needs to use double-stranded helical substrates having different structures. Here, we provide a detailed structure–function analysis of human Polα's interaction with dNTPs and DNA templates primed with RNA, chimeric RNA–DNA, or DNA. We report the crystal structures of two ternary complexes of the Polα catalytic domain containing dCTP, a DNA template, and either a DNA or an RNA primer. Unexpectedly, in the ternary complex with a DNA:DNA duplex and dCTP, the “fingers” subdomain of Polα is in the open conformation. Polα induces conformational changes in the DNA and hybrid duplexes to produce the universal double helix form. Furthermore, pre-steady-state kinetic studies indicated for both duplex types that chemical catalysis rather than product release is the rate-limiting step. Moreover, human Polα extended DNA primers with higher efficiency but lower processivity than it did with RNA and chimeric primers. Polα has a substantial propensity to make errors during DNA synthesis, and we observed that its fidelity depends on the type of sugar at the primer 3'-end. A detailed structural comparison of Polα with other replicative DNA polymerases disclosed common features and some differences, which may reflect the specialization of each polymerase in genome replication.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS); Cancer Center Support Grant; USDOE Office of Science (SC); Fred and Pamela Buffett Cancer Center Support Grant

Grant/Contract Number:: AC02–06CH11357; GM101167; GM49551; 5T32GM06754 3-12; P30CA036727; P41 GM103403; AC02-06CH11357; INBRE-P20GM103427-14; COBRE-1P30GM110768-01

OSTI ID:: 1769427

Alternate ID(s):: OSTI ID: 1439639

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Vol. 293 Journal Issue: 18; ISSN 0021-9258

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 18 works

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59 BASIC BIOLOGICAL SCIENCES
DNA replication
DNA polymerase
human
crystal structure
DNA-protein interaction
RNA
conformational change
chimeric RNA-DNA primer
Polα
Polδ
Polε
pre-steady-state kinetics

Title: Activity and fidelity of human DNA polymerase α depend on primer structure

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