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Structure of human DNA polymerase iota and the mechanism of DNA synthesis

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Abstract

Cellular DNA polymerases belong to several families and carry out different functions. Highly accurate replicative DNA polymerases play the major role in cell genome replication. A number of new specialized DNA polymerases were discovered at the turn of XX–XXI centuries and have been intensively studied during the last decade. Due to the special structure of the active site, these enzymes efficiently perform synthesis on damaged DNA but are characterized by low fidelity. Human DNA polymerase iota (Pol ι) belongs to the Y-family of specialized DNA polymerases and is one of the most error-prone enzymes involved in DNA synthesis. In contrast to other DNA polymerases, Pol ι is able to use noncanonical Hoogsteen interactions for nucleotide base pairing. This allows it to incorporate nucleotides opposite various lesions in the DNA template that impair Watson-Crick interactions. Based on the data of X-ray structural analysis of Pol ι in complexes with various DNA templates and dNTP substrates, we consider the structural peculiarities of the Pol ι active site and discuss possible mechanisms that ensure the unique behavior of the enzyme on damaged and undamaged DNA.

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Abbreviations

AAF:

2-acetylaminofluorene

AP site:

apurinic/apyrimidinic site

BPDE:

benzo(α)pyren-diol-epoxide

ɛ-dA:

1,N6-ethenodeoxyadenosine

dBrU:

5-bromodeoxyuridine

DNAP:

DNA polymerase

HG:

Hoogsteen interactions

O6-Me-dG:

O6-methyldeoxyguanosine

N2-Et-dG:

N2-ethyldeoxyguanosine

8-oxo-dG:

7,8-dihydro-8-oxodeoxyguanosine

WC:

Watson-Crick interactions

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  1. Institute of Molecular Genetics, Russian Academy of Sciences, pl. Kurchatova 2, 123182, Moscow, Russia

    A. V. Makarova & A. V. Kulbachinskiy

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  1. A. V. Makarova
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  2. A. V. Kulbachinskiy
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Correspondence to A. V. Makarova or A. V. Kulbachinskiy.

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Original Russian Text © A. V. Makarova, A. V. Kulbachinskiy, 2012, published in Biokhimiya, 2012, Vol. 77, No. 6, pp. 669–685.

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Makarova, A.V., Kulbachinskiy, A.V. Structure of human DNA polymerase iota and the mechanism of DNA synthesis. Biochemistry Moscow 77, 547–561 (2012). https://doi.org/10.1134/S0006297912060016

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