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 importantly radiation hypersensitive patients would be spared the consequences of excessive tissue damage if they were identified 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.
Xu
Huiling
H
Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Balakrishnan
Kuhendra
K
Malaterre
Jordane
J
Beasley
Matthew
M
Yan
Yuqian
Y
Essers
Jeroen
J
Appeldoorn
Esther
E
Tomaszewski
Jonathan M
JM
Thomaszewski
Jonathan M
JM
Vazquez
Melisa
M
Verschoor
Sandra
S
Lavin
Martin F
MF
Bertoncello
Ivan
I
Bertonchello
Ivan
I
Ramsay
Robert G
RG
McKay
Michael J
MJ
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics*; D002869:Chromosome Aberrations / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D017353:Gene Deletion; D056426:Genetic Loci / Q000235:genetics; D007421:Intestine, Small / Q000166:cytology; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D008938:Mitosis / Q000528:radiation effects; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D012854:Sister Chromatid Exchange / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects; D014916:Whole-Body Irradiation; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D016685:Mitomycin; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000097722:Cohesins; C465862:Rad21 protein, mouse