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ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition
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 w...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229844/ https://www.ncbi.nlm.nih.gov/pubmed/32297953 http://dx.doi.org/10.1093/nar/gkaa255 |
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author | Giovannini, Sara Weller, Marie-Christine Hanzlíková, Hana Shiota, Tetsuya Takeda, Shunichi Jiricny, Josef |
author_facet | Giovannini, Sara Weller, Marie-Christine Hanzlíková, Hana Shiota, Tetsuya Takeda, Shunichi Jiricny, Josef |
author_sort | Giovannini, Sara |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7229844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72298442020-05-21 ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition Giovannini, Sara Weller, Marie-Christine Hanzlíková, Hana Shiota, Tetsuya Takeda, Shunichi Jiricny, Josef Nucleic Acids Res Genome Integrity, Repair and Replication 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. Oxford University Press 2020-05-21 2020-04-16 /pmc/articles/PMC7229844/ /pubmed/32297953 http://dx.doi.org/10.1093/nar/gkaa255 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Giovannini, Sara Weller, Marie-Christine Hanzlíková, Hana Shiota, Tetsuya Takeda, Shunichi Jiricny, Josef ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition |
title | ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition |
title_full | ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition |
title_fullStr | ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition |
title_full_unstemmed | ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition |
title_short | ATAD5 deficiency alters DNA damage metabolism and sensitizes cells to PARP inhibition |
title_sort | atad5 deficiency alters dna damage metabolism and sensitizes cells to parp inhibition |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229844/ https://www.ncbi.nlm.nih.gov/pubmed/32297953 http://dx.doi.org/10.1093/nar/gkaa255 |
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