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

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 +/2 animals exhibited sensitivity considerably greater than control littermates when challenged with whole body irradiation (WBI). Importantly, Rad21 +/2 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.

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

“…There are a number of mechanistic links between MYC, RAD21, BETs, and CHK1. MYC and RAD21 play a role in RS and the DNA damage response (DDR) pathways [92,93]. MYC, a transcription factor involved in the pathogenesis of OS, has been known to be overexpressed and amplified in localized and metastatic OS, and contributes to therapeutic resistance of the disease [47,94].…”

Rad21 Haploinsufficiency Prevents ALT-Associated Phenotypes in Zebrafish Brain Tumors

“…Interestingly, Rad21 mutant cells have been shown to be defective in HR [11], and haploinsufficiency of Rad21 in mice induces impairment of DDR. This demonstrated that Rad21 is critical in promoting HR-mediated DNA damage repair [12].…”

“…RAD21 is believed to function in sister chromatid alignment as part of the cohesin complex. By holding sister chromatids together, RAD21 and the cohesin complex can facilitate the repair of DNA damage incurred during DNA replication [11,12]. Therefore, we asked whether rad21a haploinsufficiency, which prevents ALT, was accompanied by a change of telomeric DNA damage, possibly through DNA damage repair by HR.…”

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

“…Cohesin-deficient cancers cells have increased sensitivity to ionizating radiation, owing to cohesin's role in DNA double-strand break repair [15,193]. Therefore, using DNAdamaging agents to further block the compromised DNA repair pathway of cohesin mutant cells has potential for selective inhibition of these cells (Figure 3).…”