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Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice
Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and imp...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920816/ https://www.ncbi.nlm.nih.gov/pubmed/20711430 http://dx.doi.org/10.1371/journal.pone.0012112 |
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author | Xu, Huiling Balakrishnan, Kuhendra Malaterre, Jordane Beasley, Matthew Yan, Yuqian Essers, Jeroen Appeldoorn, Esther Thomaszewski, Jonathan M. Vazquez, Melisa Verschoor, Sandra Lavin, Martin F. Bertonchello, Ivan Ramsay, Robert G. McKay, Michael J. |
author_facet | Xu, Huiling Balakrishnan, Kuhendra Malaterre, Jordane Beasley, Matthew Yan, Yuqian Essers, Jeroen Appeldoorn, Esther Thomaszewski, Jonathan M. Vazquez, Melisa Verschoor, Sandra Lavin, Martin F. Bertonchello, Ivan Ramsay, Robert G. McKay, Michael J. |
author_sort | Xu, Huiling |
collection | PubMed |
description | Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were indentified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21(+/−) animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21(+/−) animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues. |
format | Text |
id | pubmed-2920816 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29208162010-08-13 Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice Xu, Huiling Balakrishnan, Kuhendra Malaterre, Jordane Beasley, Matthew Yan, Yuqian Essers, Jeroen Appeldoorn, Esther Thomaszewski, Jonathan M. Vazquez, Melisa Verschoor, Sandra Lavin, Martin F. Bertonchello, Ivan Ramsay, Robert G. McKay, Michael J. PLoS One Research Article Approximately half of cancer-affected patients receive radiotherapy (RT). The doses delivered have been determined upon empirical experience based upon average radiation responses. Ideally higher curative radiation doses might be employed in patients with genuinely normal radiation responses and importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were indentified before treatment. Rad21 is an integral subunit of the cohesin complex, which regulates chromosome segregation and DNA damage responses in eukaryotes. We show here, by targeted inactivation of this key cohesin component in mice, that Rad21 is a DNA-damage response gene that markedly affects animal and cell survival. Biallelic deletion of Rad21 results in early embryonic death. Rad21 heterozygous mutant cells are defective in homologous recombination (HR)-mediated gene targeting and sister chromatid exchanges. Rad21(+/−) animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21(+/−) animals are significantly more sensitive to WBI than Atm heterozygous mutant mice. Since supralethal WBI of mammals most typically leads to death via damage to the gastrointestinal tract (GIT) or the haematopoietic system, we determined the functional status of these organs in the irradiated animals. We found evidence for GIT hypersensitivity of the Rad21 mutants and impaired bone marrow stem cell clonogenic regeneration. These data indicate that Rad21 gene dosage is critical for the ionising radiation (IR) response. Rad21 mutant mice thus represent a new mammalian model for understanding the molecular basis of irradiation effects on normal tissues and have important implications in the understanding of acute radiation toxicity in normal tissues. Public Library of Science 2010-08-12 /pmc/articles/PMC2920816/ /pubmed/20711430 http://dx.doi.org/10.1371/journal.pone.0012112 Text en Xu et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Xu, Huiling Balakrishnan, Kuhendra Malaterre, Jordane Beasley, Matthew Yan, Yuqian Essers, Jeroen Appeldoorn, Esther Thomaszewski, Jonathan M. Vazquez, Melisa Verschoor, Sandra Lavin, Martin F. Bertonchello, Ivan Ramsay, Robert G. McKay, Michael J. Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice |
title |
Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice |
title_full |
Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice |
title_fullStr |
Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice |
title_full_unstemmed |
Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice |
title_short |
Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice |
title_sort | rad21-cohesin haploinsufficiency impedes dna repair and enhances gastrointestinal radiosensitivity in mice |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920816/ https://www.ncbi.nlm.nih.gov/pubmed/20711430 http://dx.doi.org/10.1371/journal.pone.0012112 |
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