Chanet R, Baille D, Golinelli-Cohen MP, Riquier S, Guittet O, Lepoivre M, Huang ME, Vernis L

B-type eukaryotic polymerases contain a [4Fe-4S] cluster in their C-terminus domain, whose role is not fully understood yet. Among them, DNA polymerase delta (Pol?) plays an essential role in chromosomal DNA replication, mostly during lagging strand synthesis. Previous in vitro work suggested that the Fe-S cluster in Pol? is required ...

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for efficient binding of the Pol31 subunit, ensuring stability of the Pol? complex. Here we analyzed the in vivo consequences resulting from an impaired coordination of the Fe-S cluster in Pol?. We show that a single substitution of the very last cysteine coordinating the cluster by a serine is responsible for the generation of massive DNA damage during S phase, leading to checkpoint activation, requirement of homologous recombination for repair, and ultimately to cell death when the repair capacities of the cells are overwhelmed. These data indicate that impaired Fe-S cluster coordination in Pol? is responsible for aberrant replication. More generally, Fe-S in Pol? may be compromised by various stress including anti-cancer drugs. Possible in vivo Pol? Fe-S cluster oxidation and collapse may thus occur, and we speculate this could contribute to induced genomic instability and cell death, comparable to that observed in pol3-13 cells.

Date: May. 01, 2021

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