Gene wiki reviewCohesin subunit RAD21: From biology to disease
Introduction
Since the discovery of RAD21 at the end of the last century as a principal component of chromosomal cohesin complex, numerous other functions of this important molecule have been described. During the last two decades, more than 4500 manuscripts have been published on RAD21, describing not only its canonical functions in sister chromatids cohesion and DNA damage repair but also other functions such as regulation of gene transcription, maintenance of nuclear architecture, biogenesis of centrosomes, meiosis, apoptosis, and hematopoiesis. In view of these pleiotropic functions of RAD21 in a broad range of cellular processes, it is not surprising that the deregulation of RAD21 has been increasingly evident in human diseases including developmental diseases, such as cohesinopathies, and cancer. How RAD21 regulates such a diverse array of cellular functions and how RAD21 mutations cause human diseases remain unclear. This review is an attempt to provide a broad view of RAD21 with a goal to synthesize a handbook of our current knowledge of RAD21, which we expect to serve as a link between the past and the future studies in this field.
Section snippets
Identification of RAD21
rad21 encoding a 628 amino acid (aa) protein was first cloned by Birkenbihl and Subramani in 1992 by complementing the radiation sensitivity of the rad21-45 mutant fission yeast, Schizosaccharomyces pombe. They reported that rad21 not only has a role in DNA double-strand break (DSB) repair but also is essential for the mitotic growth of S. pombe. By sequencing a human immature myeloid cell line-derived complementary DNA (cDNA) library, Nomura et al. (1994) identified a cDNA encoding a homolog
RAD21 protein
RAD21 is a nuclear phospho-protein, exists in all eukaryotes, and ranges in size from 278aa in the house lizard (Gekko Japonicus) to 746aa in the killer whale (Orcinus Orca), with a median length of 631aa in most vertebrate species including humans. Immunofluorescence microscopy and Western blot analysis collectively revealed nuclear expression of a 120 kDa protein in human and mouse, which was higher than the predicted 68 kDa, most likely due to post-translational modifications, including
RAD21 functions
RAD21 plays multiple physiological roles in diverse cellular functions (Fig. 5). The primary function of RAD21 is in the repair of DNA DSBs, as well as in sister chromatid cohesion during mitosis. As a subunit of the cohesin complex, RAD21 is involved in sister chromatid cohesion from the time of DNA replication in S phase to their segregation in mitosis, a function that is evolutionarily conserved and essential for proper chromosome segregation, chromosomal architecture, post-replicative DNA
RAD21 animal models
Mutant mouse and zebrafish models of Rad21 have been reported (Seitan et al., 2011, Bonora et al., 2015). Biallelic deletion of cohesin subunits results in cell death (Guacci et al., 1997, Michaelis et al., 1997, Heo et al., 1998). As in yeast, the homozygous deletion of Rad21 in mice is embryonically lethal, but heterozygous animals are viable with no significant phenotypes. Using a tissue-specific Cre-recombinase (CD4-Cre), Seitan et al. (2011) have generated a thymocyte-specific deletion of
Cohesinopathies
Cohesinopathies are a variety of rare genetic human diseases triggered by the mutations in the core subunits of cohesin complex or regulators that participate in cohesin complex dynamics. Cornelia de Lange syndrome (CdLS, OMIM 122470, 300590, 610759, 614701, 300882) is one of the best-known cohesinopathies (Barbero, 2013). CdLS is a rare, clinically variable and genetically heterogeneous disorder, with an estimated occurrence in 0.5–10 every 100,000 births (Barisic et al., 2008, Kline et al.,
Concluding statement
To conclude, RAD21, an important component of the cohesin complex, is an evolutionarily conserved protein. It is highly similar to the gene product of S. pombe rad21, a gene involved in the repair of DNA DSBs, as well as in chromatid cohesion during mitosis. In addition to playing roles in maintaining the chromatin architecture during the normal cell cycle and DNA DSB repair, RAD21 is also linked to an array of other functions, including apoptosis and hematopoiesis. Germline heterozygous or
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series--a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE. This work was supported by the Cancer Prevention and Research Institute of Texas Grant # DP150064, and RP190002. We also thank
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