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Replisome Disassembly At The Termination Of Eukaryotic Replication Forks
Author(s) -
Gambus Agnieszka
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.111.3
Subject(s) - replisome , helicase , pre replication complex , control of chromosome duplication , minichromosome maintenance , biology , origin recognition complex , microbiology and biotechnology , eukaryotic dna replication , dna replication , genetics , dna re replication , dna , gene , rna
To ensure duplication of the whole genome DNA replication initiates from thousands of origins of replication. The pre‐loaded inactive helicase (Mcm2‐7 double hexameric complexes) becomes activated during replication initiation by loading of additional components: Cdc45 and GINS in a carefully regulated process. The progressing replication fork moves through the chromatin until it encounters fork from the neighboring origin. During the termination of replication forks the replisomes disassemble and topisomerase II resolves the daughter DNA molecules. If not resolved properly, the terminating forks are at risk of stalling and fork reversal, leading to DNA damage and genomic instability. Using the Xenopus laevis egg extract system, we have shown (Priego Moreno et al. Science 2014) that blocking polyubiquitylation results in the prolonged association of the active helicase with replicating chromatin. It was accompanied by a defect in replication forks termination leading to conclusion that polyubiquitylation is essential for the disassembly of the active helicase at the termination of replication forks. The Mcm7 subunit of the Mcm2‐7 complex was the only component of the active helicase that we found polyubiquitylated during S‐phase and its ubiquitylation was blocked when forks could not terminate. Finally, disassembly of the helicase was dependent on p97/VCP/Cdc48 segregase activity. This process of replisome dissolution is very well conserved through evolution (Maric et al. Science 2014), however, the ubiquitin ligase driving ubiquitylation of replicative helicase is not. I will present, therefore, our recent findings on the identity of the enzyme ubiquitylating Mcm7 in higher eukaryotes. Support or Funding Information This work was funded by MRC CDA Fellowship and Lister Institute Research Award for A.G.