Replication factor C (RFC), a heteropentamer of RFC1-5, loads PCNA onto DNA during replication and repair. Once DNA synthesis has ceased, PCNA must be unloaded. Recent findings assign the uloader role primarily to an RFC-like (RLC) complex, in which the largest RFC subunit, RFC1, has been replaced with ATAD5 (ELG1 in Saccharomyces cerevisiae). ATAD5-RLC appears to be indispensable, given that Atad5 knock-out leads to embryonic lethality. In order to learn how the retention of PCNA on DNA might interfere with normal DNA metabolism, we studied the response of ATAD5-depleted cells to several genotoxic agents. We show that ATAD5 deficiency leads to hypersensitivity to methyl methanesulphonate (MMS), camptothecin (CPT) and mitomycin C (MMC), agents that hinder the progression of replication forks. We further show that ATAD5-depleted cells are sensitive to poly(ADP)ribose polymerase (PARP) inhibitors and that the processing of spontaneous oxidative DNA damage contributes towards this sensitivity. We posit that PCNA molecules trapped on DNA interfere with the correct metabolism of arrested replication forks, phenotype reminiscent of defective homologous recombination (HR). As Atad5 heterozygous mice are cancer-prone and as ATAD5 mutations have been identified in breast and endometrial cancers, our finding may open a path towards the therapy of these tumours.
- MeSH
- ATPázy spojené s různými buněčnými aktivitami genetika metabolismus MeSH
- buněčné linie MeSH
- chromatin enzymologie MeSH
- DNA vazebné proteiny genetika metabolismus MeSH
- DNA metabolismus MeSH
- ftalaziny farmakologie MeSH
- kur domácí MeSH
- mutageny toxicita MeSH
- nádorové buněčné linie MeSH
- nestabilita genomu MeSH
- PARP inhibitory farmakologie MeSH
- piperaziny farmakologie MeSH
- poly(ADP-ribosa)polymerasa 1 metabolismus MeSH
- poškození DNA * MeSH
- protinádorové látky farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
