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Nucleic Acids Res 2021 Sep 27;4917:9851-9869. doi: 10.1093/nar/gkab756.
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Polo-like kinase 1 (Plk1) regulates DNA replication origin firing and interacts with Rif1 in Xenopus.

Ciardo D , Haccard O , Narassimprakash H , Cornu D , Guerrera IC , Goldar A , Marheineke K .

The activation of eukaryotic DNA replication origins needs to be strictly controlled at multiple steps in order to faithfully duplicate the genome and to maintain its stability. How the checkpoint recovery and adaptation protein Polo-like kinase 1 (Plk1) regulates the firing of replication origins during non-challenged S phase remained an open question. Using DNA fiber analysis, we show that immunodepletion of Plk1 in the Xenopus in vitro system decreases replication fork density and initiation frequency. Numerical analyses suggest that Plk1 reduces the overall probability and synchrony of origin firing. We used quantitative chromatin proteomics and co-immunoprecipitations to demonstrate that Plk1 interacts with firing factors MTBP/Treslin/TopBP1 as well as with Rif1, a known regulator of replication timing. Phosphopeptide analysis by LC/MS/MS shows that the C-terminal domain of Rif1, which is necessary for its repressive action on origins through protein phosphatase 1 (PP1), can be phosphorylated in vitro by Plk1 on S2058 in its PP1 binding site. The phosphomimetic S2058D mutant interrupts the Rif1-PP1 interaction and modulates DNA replication. Collectively, our study provides molecular insights into how Plk1 regulates the spatio-temporal replication program and suggests that Plk1 controls origin activation at the level of large chromatin domains in vertebrates.

PubMed ID: 34469577
PMC ID: PMC8464078
Article link: Nucleic Acids Res
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cdc45 cdc7 chek1 ctrl lss mcm4 mtbp npy4r orc2 plk1 rif1 ticrr topbp1
GO keywords: DNA replication checkpoint [+]
Antibodies: H3f3a Ab33

Article Images: [+] show captions
References [+] :
, UniProt: a worldwide hub of protein knowledge. 2020, Pubmed