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ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition
S. Giovannini, MC. Weller, H. Hanzlíková, T. Shiota, S. Takeda, J. Jiricny,
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
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PubMed
32297953
DOI
10.1093/nar/gkaa255
Knihovny.cz E-resources
- MeSH
- ATPases Associated with Diverse Cellular Activities genetics metabolism MeSH
- Cell Line MeSH
- Chromatin enzymology MeSH
- DNA-Binding Proteins genetics metabolism MeSH
- DNA metabolism MeSH
- Phthalazines pharmacology MeSH
- Chickens MeSH
- Mutagens toxicity MeSH
- Cell Line, Tumor MeSH
- Genomic Instability MeSH
- Poly(ADP-ribose) Polymerase Inhibitors pharmacology MeSH
- Piperazines pharmacology MeSH
- Poly (ADP-Ribose) Polymerase-1 metabolism MeSH
- DNA Damage * MeSH
- Antineoplastic Agents pharmacology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
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- $a Giovannini, Sara $u Institute of Molecular Life Sciences of the University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Institute of Molecular Cancer Research of the University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Institute of Biochemistry of the Swiss Federal Institute of Technology, Otto-Stern-Weg 3, 8093 Zurich, Switzerland.
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- $a 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.
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