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Increased contribution of DNA polymerase delta to the leading strand replication in yeast with an impaired CMG helicase complex

Dmowski, Michal and Jedrychowska, Malgorzata and Makiela-Dzbenska, Karolina and Denkiewicz-Kruk, Milena and Sharma, Sushma and Chabes, Andrei and Araki, Hiroyuki and Fijalkowska, Iwona J. (2022) Increased contribution of DNA polymerase delta to the leading strand replication in yeast with an impaired CMG helicase complex. DNA Repair, 110 (103272). p. 103272. ISSN 1568-7864

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Official URL: https://www.sciencedirect.com/science/article/pii/...

Abstract

DNA replication is performed by replisome proteins, which are highly conserved from yeast to humans. The CMG [Cdc45-Mcm2–7-GINS(Psf1–3, Sld5)] helicase unwinds the double helix to separate the leading and lagging DNA strands, which are replicated by the specialized DNA polymerases epsilon (Pol ε) and delta (Pol δ), respectively. This division of labor was confirmed by both genetic analyses and in vitro studies. Exceptions from this rule were described mainly in cells with impaired catalytic polymerase ε subunit. The central role in the recruitment and establishment of Pol ε on the leading strand is played by the CMG complex assembled on DNA during replication initiation. In this work we analyzed the consequences of impaired functioning of the CMG complex for the di�vision labor between DNA polymerases on the two replicating strands. We showed in vitro that the GINSPsf1–1 complex poorly bound the Psf3 subunit. In vivo, we observed increased rates of L612M Pol δ-specific mutations during replication of the leading DNA strand in psf1–1 cells. These findings indicated that defective functioning of GINS impaired leading strand replication by Pol ε and necessitated involvement of Pol δ in the synthesis on this strand with a possible impact on the distribution of mutations and genomic stability. These are the first results to imply that the division of labor between the two main replicases can be severely influenced by a defective nonpolymerase subunit of the replisome.

Item Type:Article
Uncontrolled Keywords:DNA polymerase epsilon Pol ε DNA polymerase delta Pol δ CMG (Cdc45 Mcm2–7 GINS) Replication fork DNA replication fidelity Genome stability
Subjects:Q Science > Q Science (General)
Divisions:Laboratory of Mutagenesis and DNA Repair
ID Code:2139
Deposited By: dr Michał Dmowski
Deposited On:07 Feb 2022 14:40
Last Modified:07 Feb 2022 14:40

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