ACS Chemical Biology, volume 17, issue 11, pages 3238-3250
Translesion Synthesis across the N2-Ethyl-deoxyguanosine Adduct by Human PrimPol
Ghodke Pratibha P
2
,
Sudhakar Sruthi
2
,
Mishra Vipin Kumar
2
,
Manukyan Anna A
1
,
Miropolskaya Nataliya
1
,
Макарова А. В.
1
1
Publication type: Journal Article
Publication date: 2022-11-01
Journal:
ACS Chemical Biology
Quartile SCImago
Q1
Quartile WOS
Q2
Impact factor: 4
ISSN: 15548929, 15548937
Biochemistry
General Medicine
Molecular Medicine
Abstract
Primase-DNA polymerase (PrimPol) is involved in reinitiating DNA synthesis at stalled replication forks. PrimPol also possesses DNA translesion (TLS) activity and bypasses several endogenous nonbulky DNA lesions in vitro. Little is known about the TLS activity of PrimPol across bulky carcinogenic adducts. We analyzed the DNA polymerase activity of human PrimPol on DNA templates with seven N2-dG lesions of different steric bulkiness. In the presence of Mg2+ ions, bulky N2-isobutyl-dG, N2-benzyl-dG, N2-methyl(1-naphthyl)-dG, N2-methyl(9-anthracenyl)-dG, N2-methyl(1-pyrenyl)-dG, and N2-methyl(1,3-dimethoxyanthraquinone)-dG adducts fully blocked PrimPol activity. At the same time, PrimPol incorporated complementary deoxycytidine monophosphate (dCMP) opposite N2-ethyl-dG with moderate efficiency but did not extend DNA beyond the lesion. We also demonstrated that mutation of the Arg288 residue abrogated dCMP incorporation opposite the lesion in the presence of Mn2+ ions. When Mn2+ replaced Mg2+, PrimPol carried out DNA synthesis on all DNA templates with N2-dG adducts in standing start reactions with low efficiency and accuracy, possibly utilizing a lesion "skipping" mechanism. The TLS activity of PrimPol opposite N2-ethyl-dG but not bulkier adducts was stimulated by accessory proteins, polymerase delta-interacting protein 2 (PolDIP2), and replication protein A (RPA). Molecular dynamics studies demonstrated the absence of stable interactions with deoxycytidine triphosphate (dCTP), large reactions, and C1'-C1' distances for the N2-isobutyl-dG and N2-benzyl-dG PrimPol complexes, suggesting that the size of the adduct is a limiting factor for efficient TLS across minor groove adducts by PrimPol.
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Bioscience Reports
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Bioscience Reports
1 publication, 25%
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Biochemistry (Moscow)
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Biochemistry (Moscow)
1 publication, 25%
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Journal of Molecular Biology
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Journal of Molecular Biology
1 publication, 25%
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Springer Nature
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Springer Nature
1 publication, 25%
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Pleiades Publishing
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Pleiades Publishing
1 publication, 25%
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Elsevier
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Elsevier
1 publication, 25%
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Boldinova E. O. et al. Translesion Synthesis across the N2-Ethyl-deoxyguanosine Adduct by Human PrimPol // ACS Chemical Biology. 2022. Vol. 17. No. 11. pp. 3238-3250.
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Boldinova E. O., Ghodke P. P., Sudhakar S., Mishra V. K., Manukyan A. A., Miropolskaya N., Pradeepkumar P., Макарова А. В. Translesion Synthesis across the N2-Ethyl-deoxyguanosine Adduct by Human PrimPol // ACS Chemical Biology. 2022. Vol. 17. No. 11. pp. 3238-3250.
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TY - JOUR
DO - 10.1021/acschembio.2c00717
UR - https://doi.org/10.1021%2Facschembio.2c00717
TI - Translesion Synthesis across the N2-Ethyl-deoxyguanosine Adduct by Human PrimPol
T2 - ACS Chemical Biology
AU - Boldinova, Elizaveta O
AU - Ghodke, Pratibha P
AU - Sudhakar, Sruthi
AU - Mishra, Vipin Kumar
AU - Manukyan, Anna A
AU - Miropolskaya, Nataliya
AU - Pradeepkumar, P.I.
AU - Макарова, А. В.
PY - 2022
DA - 2022/11/01 00:00:00
PB - American Chemical Society (ACS)
SP - 3238-3250
IS - 11
VL - 17
SN - 1554-8929
SN - 1554-8937
ER -
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@article{2022_Boldinova,
author = {Elizaveta O Boldinova and Pratibha P Ghodke and Sruthi Sudhakar and Vipin Kumar Mishra and Anna A Manukyan and Nataliya Miropolskaya and P.I. Pradeepkumar and А. В. Макарова},
title = {Translesion Synthesis across the N2-Ethyl-deoxyguanosine Adduct by Human PrimPol},
journal = {ACS Chemical Biology},
year = {2022},
volume = {17},
publisher = {American Chemical Society (ACS)},
month = {nov},
url = {https://doi.org/10.1021%2Facschembio.2c00717},
number = {11},
pages = {3238--3250},
doi = {10.1021/acschembio.2c00717}
}
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MLA
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Boldinova, Elizaveta O., et al. “Translesion Synthesis across the N2-Ethyl-deoxyguanosine Adduct by Human PrimPol.” ACS Chemical Biology, vol. 17, no. 11, Nov. 2022, pp. 3238-3250. https://doi.org/10.1021%2Facschembio.2c00717.