Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice

Xu, HL, Balakrishnan, K, Malaterre, J, Beasley, M, Yan, YQ, Essers, J, Appeldoorn, E, Thomaszewski, JM, Vazquez, M, Verschoor, S, Lavin, MF, Bertonchello, I, Ramsay, RG and Mckay, MJ (2010) Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice. PLoS One, 5 8: e12112-1-e12112-15. doi:10.1371/journal.pone.0012112

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Author Xu, HL
Balakrishnan, K
Malaterre, J
Beasley, M
Yan, YQ
Essers, J
Appeldoorn, E
Thomaszewski, JM
Vazquez, M
Verschoor, S
Lavin, MF
Bertonchello, I
Ramsay, RG
Mckay, MJ
Title Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice
Formatted title
Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2010-01-01
Sub-type Article (original research)
DOI 10.1371/journal.pone.0012112
Open Access Status DOI
Volume 5
Issue 8
Start page e12112-1
End page e12112-15
Total pages 15
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2011
Language eng
Formatted abstract
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.
© 2010 Xu et al.
Keyword Cohesin
Rad21
DNA repair
Mice
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article # e12112

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2011 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 39 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 22 Feb 2011, 20:14:42 EST by Caroline Irle on behalf of UQ Centre for Clinical Research