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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.

Rad21-Cohesin Haploinsufficiency Impedes DNA Repair and Enhances Gastrointestinal Radiosensitivity in Mice