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Volume 21
Issue 24
10.3390/ijms21249484
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Article

Recombination and Pol ζ Rescue Defective DNA Replication upon Impaired CMG Helicase—Pol ε Interaction

by
Milena Denkiewicz-Kruk
1,
Malgorzata Jedrychowska
1,
Shizuko Endo
2,
Hiroyuki Araki
2,
Piotr Jonczyk
1,†,
Michal Dmowski
1,* and
Iwona J. Fijalkowska
1,*
1
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
2
National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan
*
Authors to whom correspondence should be addressed.
†
In memoriam. This author passed away after the acceptance of this article
Int. J. Mol. Sci. 2020, 21(24), 9484; https://doi.org/10.3390/ijms21249484
Received: 20 November 2020 / Revised: 6 December 2020 / Accepted: 9 December 2020 / Published: 13 December 2020
(This article belongs to the Special Issue Genome Maintenance and Cancer)
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Abstract

The CMG complex (Cdc45, Mcm2–7, GINS (Psf1, 2, 3, and Sld5)) is crucial for both DNA replication initiation and fork progression. The CMG helicase interaction with the leading strand DNA polymerase epsilon (Pol ε) is essential for the preferential loading of Pol ε onto the leading strand, the stimulation of the polymerase, and the modulation of helicase activity. Here, we analyze the consequences of impaired interaction between Pol ε and GINS in Saccharomyces cerevisiae cells with the psf1-100 mutation. This significantly affects DNA replication activity measured in vitro, while in vivo, the psf1-100 mutation reduces replication fidelity by increasing slippage of Pol ε, which manifests as an elevated number of frameshifts. It also increases the occurrence of single-stranded DNA (ssDNA) gaps and the demand for homologous recombination. The psf1-100 mutant shows elevated recombination rates and synthetic lethality with rad52Δ. Additionally, we observe increased participation of DNA polymerase zeta (Pol ζ) in DNA synthesis. We conclude that the impaired interaction between GINS and Pol ε requires enhanced involvement of error-prone Pol ζ, and increased participation of recombination as a rescue mechanism for recovery of impaired replication forks. View Full-Text
Keywords: CMGE helicase-polymerase complex; GINS complex; PSF1/GINS1; DNA polymerase epsilon; Pol ε; polymerase zeta; Pol ζ; recombination; DRIM; DNA replication fidelity; genetic instability; repeat tracts instability CMGE helicase-polymerase complex; GINS complex; PSF1/GINS1; DNA polymerase epsilon; Pol ε; polymerase zeta; Pol ζ; recombination; DRIM; DNA replication fidelity; genetic instability; repeat tracts instability
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MDPI and ACS Style

Denkiewicz-Kruk, M.; Jedrychowska, M.; Endo, S.; Araki, H.; Jonczyk, P.; Dmowski, M.; Fijalkowska, I.J. Recombination and Pol ζ Rescue Defective DNA Replication upon Impaired CMG Helicase—Pol ε Interaction. Int. J. Mol. Sci. 2020, 21, 9484. https://doi.org/10.3390/ijms21249484

AMA Style

Denkiewicz-Kruk M, Jedrychowska M, Endo S, Araki H, Jonczyk P, Dmowski M, Fijalkowska IJ. Recombination and Pol ζ Rescue Defective DNA Replication upon Impaired CMG Helicase—Pol ε Interaction. International Journal of Molecular Sciences. 2020; 21(24):9484. https://doi.org/10.3390/ijms21249484

Chicago/Turabian Style

Denkiewicz-Kruk, Milena, Malgorzata Jedrychowska, Shizuko Endo, Hiroyuki Araki, Piotr Jonczyk, Michal Dmowski, and Iwona J. Fijalkowska. 2020. "Recombination and Pol ζ Rescue Defective DNA Replication upon Impaired CMG Helicase—Pol ε Interaction" International Journal of Molecular Sciences 21, no. 24: 9484. https://doi.org/10.3390/ijms21249484

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