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+/− 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.

Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing

“…41 Furthermore, it also directly regulates transcription of genes implicated in pluripotency, cell proliferation, and differentiation, 37 and monoallelic loss of RAD21 has been associated with impaired bone marrow stem cell clonogenic regeneration, while homozygous deletion results in early embryonic death. 42 In addition, in siRNA-based screens, RAD21 was recently also identified as a functional epigenetic silencing factor along with other genes like DNMT3A, and TRIM24, both of which are also mutated in AML. 43 The chromosomal coordinates refer to the human reference genome hg19 (GRCh37).…”

Deregulation of RAD21 and RUNX1 expression in endometrial cancer

“…The examined markers correlated with each other, partially unraveling the network of genes involved in endometrial tumorigenesis. Findings of previous studies have suggested that the decreased expression of cohesins results in an inappropriate increase in homologous recombination which may drive tumorigenesis through the promotion of genomic instability, such as loss of heterozygosity (15,33,34).…”

“…The deregulation of cohesin expression and cohesin-regulated genes is common in numerous types of human cancer (8)(9)(10)(11)(12)(13), including endometrial cancer (14). Furthermore, cohesin-defective cells have been discovered to be sensitive to ionizing radiation and DNA-damaging drugs (8,15).…”

RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in kras mutant colorectal carcinomas

“…To date, both in vitro and in vivo data demonstrate that RAD21 expression influences cellular sensitivity to DNA-damaging agents such as those used in chemotherapy or chemoradiotherapy (Atienza et al, 2005;Bauerschmidt et al, 2010;Xu et al, 2010;Xu et al, 2011a, b). An increased susceptibility of cancer cell lines to conventional chemotherapeutics was demonstrated following knockdown of RAD21 or other cohesin gene (Atienza et al, 2005;Xu et al, 2011b;Supernat et al, 2012).…”

“…During the G1 phases of the cell cycle, the cohesin complex is thought to form a ring and entrap DNA helices and, with the aid of several accessory and regulatory proteins, facilitates binding of newly formed sister chromosomes and appropriate chromosome segregation during anaphase (Haering et al, 2008). The cohesin complex is also implicated in several other important processes including homologous recombinational repair or DNA damage (Birkenbihl and Subramani, 1992;Nasmyth et al, 2001;Sonoda et al, 2001;Watrin and Peters, 2006), in particular double-stranded breaks (Birkenbihl and Subramani, 1992;Bauerschmidt et al, 2010;Xu et al, 2010), cell cycle checkpoint control (Watrin and Peters, 2009), chromatin remodelling (Hakimi et al, 2002), gene regulation (Supernat et al, 2012) and prevention of read-through transcription. Presence of this versatile complex in subcellular locations outside the nucleus and within extracellular matrix has also been observed; however, the exact purpose of cohesin in these instances is unknown.…”