期刊
DNA REPAIR
卷 110, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.dnarep.2022.103272
关键词
DNA polymerase epsilon; Pol epsilon; DNA polymerase delta; Pol epsilon; CMG (Cdc45 Mcm2-7 GINS); Replication fork; DNA replication fidelity; Genome stability
资金
- National Science Centre, Poland [2015/17/B/NZ1/00850]
- Swedish Cancer Society
- Swedish Research Council
DNA replication is facilitated by replisome proteins, including the CMG helicase. Impaired functioning of the GINS complex can lead to defects in the replication of the leading DNA strand and increased mutation rates.
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 epsilon) and delta (Pol delta), 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 c subunit. The central role in the recruitment and establishment of Pol c 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 division labor between DNA polymerases on the two replicating strands. We showed in vitro that the GINS(Psf1-1) complex poorly bound the Psf3 subunit. In vivo, we observed increased rates of L612M Pol 6-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 c and necessitated involvement of Pol 6 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.
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