RAD21

rad21 was first cloned by Birkenbihl and Subramani in 1992 {{cite journal | vauthors = Birkenbihl RP, Subramani S | title = Cloning and characterization of rad21 an essential gene of Schizosaccharomyces pombe involved in DNA double-strand-break repair | journal = Nucleic Acids Research | volume = 20 | issue = 24 | pages = 6605–11 | date = December 1992 | pmid = 1480481 | pmc = 334577 | doi = 10.1093/nar/20.24.6605 }} by complementing the radiation sensitivity of the rad21-45 mutant fission yeast, Schizosaccharomyces pombe, and the murine and human homologs of S. pombe rad21 were cloned by McKay, Troelstra, van der Spek, Kanaar, Smit, Hagemeijer, Bootsma and Hoeijmakers.{{cite journal | vauthors = McKay MJ, Troelstra C, van der Spek P, Kanaar R, Smit B, Hagemeijer A, Bootsma D, Hoeijmakers JH | title = Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse | journal = Genomics | volume = 36 | issue = 2 | pages = 305–15 | date = September 1996 | pmid = 8812457 | doi = 10.1006/geno.1996.0466 | url = http://repub.eur.nl/pub/3107 | hdl = 1765/3107 | hdl-access = free }}  The human RAD21 (hRAD21) gene is located on the long (q) arm of chromosome 8 at position 24.11 (8q24.11).{{cite journal | vauthors = Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S | title = Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1 | journal = DNA Research | volume = 1 | issue = 5 | pages = 223–9 | date = 1994-01-01 | pmid = 7584044 | doi = 10.1093/dnares/1.5.223 | url = https://academic.oup.com/dnaresearch/article-lookup/doi/10.1093/dnares/1.5.223 | doi-access = free }}  In 1997, RAD21 was independently discovered by two groups to be a major component of the chromosomal cohesin complex,{{cite journal | vauthors = Guacci V, Koshland D, Strunnikov A | title = A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae | journal = Cell | volume = 91 | issue = 1 | pages = 47–57 | date = October 1997 | pmid = 9335334 | pmc = 2670185 | doi = 10.1016/S0092-8674(01)80008-8 }}{{cite journal | vauthors = Michaelis C, Ciosk R, Nasmyth K | title = Cohesins: chromosomal proteins that prevent premature separation of sister chromatids | journal = Cell | volume = 91 | issue = 1 | pages = 35–45 | date = October 1997 | pmid = 9335333 | doi = 10.1016/S0092-8674(01)80007-6 | s2cid = 18572651 | doi-access = free }} and its dissolution by the cysteine protease Separase at the metaphase to anaphase transition results in the separation of sister chromatids and chromosomal segregation.{{cite journal | vauthors = Uhlmann F, Lottspeich F, Nasmyth K | title = Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1 | journal = Nature | volume = 400 | issue = 6739 | pages = 37–42 | date = July 1999 | pmid = 10403247 | doi = 10.1038/21831 | url = http://www.nature.com/articles/21831 | s2cid = 4354549 | bibcode = 1999Natur.400...37U | url-access = subscription }}

RAD21, belongs to a superfamily of eukaryotic and prokaryotic proteins called a-Kleisins,{{cite journal | vauthors = Nasmyth K, Haering CH | title = The structure and function of SMC and kleisin complexes | journal = Annual Review of Biochemistry | volume = 74 | issue = 1 | pages = 595–648 | date = June 2005 | pmid = 15952899 | doi = 10.1146/annurev.biochem.74.082803.133219 }} is a nuclear phospho-protein, 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.  RAD21 proteins are most conserved at the N-terminus (NT) and C-terminus (CT), which bind to SMC3 and SMC1, respectively. The STAG domain in the middle of RAD21, which binds to SCC3 (SA1/SA2), is also conserved (Figure 1). These proteins have nuclear localization signals, an acidic-basic stretch and an acidic stretch (Figure 1), which is consistent with a chromatin-binding role. RAD21 is cleaved by several proteases including Separase{{cite journal | vauthors = Hauf S, Waizenegger IC, Peters JM | title = Cohesin cleavage by separase required for anaphase and cytokinesis in human cells | journal = Science | volume = 293 | issue = 5533 | pages = 1320–3 | date = August 2001 | pmid = 11509732 | doi = 10.1126/science.1061376 | bibcode = 2001Sci...293.1320H | s2cid = 46036132 }}{{cite journal | vauthors = Uhlmann F, Wernic D, Poupart MA, Koonin EV, Nasmyth K | title = Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast | journal = Cell | volume = 103 | issue = 3 | pages = 375–86 | date = October 2000 | pmid = 11081625 | doi = 10.1016/S0092-8674(00)00130-6 | s2cid = 2667617 | doi-access = free }} and Calcium-dependent cysteine endopeptidase Calpain-1{{cite journal | vauthors = Panigrahi AK, Zhang N, Mao Q, Pati D | title = Calpain-1 cleaves Rad21 to promote sister chromatid separation | journal = Molecular and Cellular Biology | volume = 31 | issue = 21 | pages = 4335–47 | date = November 2011 | pmid = 21876002 | pmc = 3209327 | doi = 10.1128/MCB.06075-11 }} during mitosis and Caspases during apoptosis.{{cite journal | vauthors = Chen F, Kamradt M, Mulcahy M, Byun Y, Xu H, McKay MJ, Cryns VL | title = Caspase proteolysis of the cohesin component RAD21 promotes apoptosis | journal = The Journal of Biological Chemistry | volume = 277 | issue = 19 | pages = 16775–81 | date = May 2002 | pmid = 11875078 | doi = 10.1074/jbc.M201322200 | doi-access = free }}{{cite journal | vauthors = Pati D, Zhang N, Plon SE | title = Linking sister chromatid cohesion and apoptosis: role of Rad21 | journal = Molecular and Cellular Biology | volume = 22 | issue = 23 | pages = 8267–77 | date = December 2002 | pmid = 12417729 | pmc = 134054 | doi = 10.1128/MCB.22.23.8267-8277.2002 }}

File:Characteristics on human RAD21. .tif

RAD21 binds to the V-shaped SMC1 and SMC3 heterodimer, forming a tripartite ring-like structure,{{cite journal | vauthors = Gligoris TG, Scheinost JC, Bürmann F, Petela N, Chan KL, Uluocak P, Beckouët F, Gruber S, Nasmyth K, Löwe J | title = Closing the cohesin ring: structure and function of its Smc3-kleisin interface | journal = Science | volume = 346 | issue = 6212 | pages = 963–7 | date = November 2014 | pmid = 25414305 | pmc = 4300515 | doi = 10.1126/science.1256917 | bibcode = 2014Sci...346..963G }} and then recruits SCC3 (SA1/SA2). The 4 element-complex is called the cohesin complex (Figure 2).  Currently, there are two major competing models of sister chromatid cohesion (Figure 2B).  The first one is the one-ring embrace model,{{cite journal | vauthors = Haering CH, Löwe J, Hochwagen A, Nasmyth K | title = Molecular architecture of SMC proteins and the yeast cohesin complex | journal = Molecular Cell | volume = 9 | issue = 4 | pages = 773–88 | date = April 2002 | pmid = 11983169 | doi = 10.1016/S1097-2765(02)00515-4 | doi-access = free }} and the second one is the dimeric handcuff-model.{{cite journal | vauthors = Zhang N, Kuznetsov SG, Sharan SK, Li K, Rao PH, Pati D | title = A handcuff model for the cohesin complex | journal = The Journal of Cell Biology | volume = 183 | issue = 6 | pages = 1019–31 | date = December 2008 | pmid = 19075111 | pmc = 2600748 | doi = 10.1083/jcb.200801157 }}{{cite journal | vauthors = Zhang N, Pati D | title = Handcuff for sisters: a new model for sister chromatid cohesion | journal = Cell Cycle | volume = 8 | issue = 3 | pages = 399–402 | date = February 2009 | pmid = 19177018 | pmc = 2689371 | doi = 10.4161/cc.8.3.7586 }} The one-ring embrace model posits that a single cohesin ring traps two sister chromatids inside, while the two-ring handcuff model proposes trapping of each chromatid individually.  According to the handcuff model, each ring has one set of RAD21, SMC1, and SMC3 molecules. The handcuff is established when two RAD21 molecules move into anti-parallel orientation that is enforced by either SA1 or SA2.

File:Figure 2 Cohesin complex and models. .tif

The N-terminal domain of RAD21 contains two α-helices that forms a three helical bundle with the coiled coil of SMC3. The central region of RAD21 is thought to be largely unstructured but contains several binding sites for regulators of cohesin. This includes a binding site for SA1 or SA2,{{cite journal | vauthors = Hara K, Zheng G, Qu Q, Liu H, Ouyang Z, Chen Z, Tomchick DR, Yu H | title = Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion | journal = Nature Structural & Molecular Biology | volume = 21 | issue = 10 | pages = 864–70 | date = October 2014 | pmid = 25173175 | pmc = 4190070 | doi = 10.1038/nsmb.2880 }} recognition motifs for separase, caspase, and calpain to cleave, as well as a region that is competitively bound by PDS5A, PDS5B or NIPBL.{{cite journal | vauthors = Petela NJ, Gligoris TG, Metson J, Lee BG, Voulgaris M, Hu B, Kikuchi S, Chapard C, Chen W, Rajendra E, Srinivisan M, Yu H, Löwe J, Nasmyth KA | title = Scc2 Is a Potent Activator of Cohesin's ATPase that Promotes Loading by Binding Scc1 without Pds5 | journal = Molecular Cell | volume = 70 | issue = 6 | pages = 1134–1148.e7 | date = June 2018 | pmid = 29932904 | pmc = 6028919 | doi = 10.1016/j.molcel.2018.05.022 }}{{cite journal | vauthors = Kikuchi S, Borek DM, Otwinowski Z, Tomchick DR, Yu H | title = Crystal structure of the cohesin loader Scc2 and insight into cohesinopathy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 44 | pages = 12444–12449 | date = November 2016 | pmid = 27791135 | pmc = 5098657 | doi = 10.1073/pnas.1611333113 | bibcode = 2016PNAS..11312444K | doi-access = free }}{{cite journal | vauthors = Muir KW, Kschonsak M, Li Y, Metz J, Haering CH, Panne D | title = Structure of the Pds5-Scc1 Complex and Implications for Cohesin Function | journal = Cell Reports | volume = 14 | issue = 9 | pages = 2116–2126 | date = March 2016 | pmid = 26923589 | doi = 10.1016/j.celrep.2016.01.078 | doi-access = free }}  The C-terminal domain of RAD21 forms a winged helix that binds two β-sheets in the Smc1 head domain.{{cite journal | vauthors = Haering CH, Schoffnegger D, Nishino T, Helmhart W, Nasmyth K, Löwe J | title = Structure and stability of cohesin's Smc1-kleisin interaction | journal = Molecular Cell | volume = 15 | issue = 6 | pages = 951–64 | date = September 2004 | pmid = 15383284 | doi = 10.1016/j.molcel.2004.08.030 | doi-access = free }}

WAPL releases cohesin from DNA by opening the SMC3-RAD21 interface thereby allowing DNA to pass out of the ring.{{cite journal | vauthors = Beckouët F, Srinivasan M, Roig MB, Chan KL, Scheinost JC, Batty P, Hu B, Petela N, Gligoris T, Smith AC, Strmecki L, Rowland BD, Nasmyth K | title = Releasing Activity Disengages Cohesin's Smc3/Scc1 Interface in a Process Blocked by Acetylation | journal = Molecular Cell | volume = 61 | issue = 4 | pages = 563–574 | date = February 2016 | pmid = 26895425 | pmc = 4769318 | doi = 10.1016/j.molcel.2016.01.026 }}  Opening of this interface is regulated by ATP-binding by the SMC subunits. This causes the ATPase head domains to dimerise and deforms the coiled coil of SMC3 therefore disrupting the binding of RAD21 to the coiled coil.{{cite journal | vauthors = Muir KW, Li Y, Weis F, Panne D | title = The structure of the cohesin ATPase elucidates the mechanism of SMC-kleisin ring opening | journal = Nature Structural & Molecular Biology | volume = 27 | issue = 3 | pages = 233–239 | date = March 2020 | pmid = 32066964 | pmc = 7100847 | doi = 10.1038/s41594-020-0379-7 }}

File:Figure 3 Functional classification of RAD21 interactors..tif

A total of 285 RAD21-interactants have been reported{{cite web | title = RAD21 cohesin complex component [Homo sapiens] | url = https://www.ncbi.nlm.nih.gov/gene/5885 | work = NCBI gene | publisher = National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine }} that function in wide range of cellular processes, including mitosis, regulation of apoptosis, chromosome dynamics, chromosomal cohesion, replication, transcription regulation, RNA processing, DNA damage response, protein modification and degradation, and cytoskeleton and cell motility (Figure 3).{{cite journal | vauthors = Panigrahi AK, Zhang N, Otta SK, Pati D | title = A cohesin-RAD21 interactome | journal = The Biochemical Journal | volume = 442 | issue = 3 | pages = 661–70 | date = March 2012 | pmid = 22145905 | doi = 10.1042/BJ20111745 | s2cid = 46097282 | url = https://portlandpress.com/biochemj/article/442/3/661/81034/A-cohesinRAD21-interactome | url-access = subscription }}

File:Figure 4 RAD21 Functions in various cellular processes. .tif

RAD21 plays multiple physiological roles in diverse cellular functions (Figure 4).  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 repair, and the prevention of inappropriate recombination between repetitive regions. RAD21 may also play a role in spindle pole assembly during mitosis {{cite journal | vauthors = Gregson HC, Schmiesing JA, Kim JS, Kobayashi T, Zhou S, Yokomori K | title = A potential role for human cohesin in mitotic spindle aster assembly | journal = The Journal of Biological Chemistry | volume = 276 | issue = 50 | pages = 47575–82 | date = December 2001 | pmid = 11590136 | doi = 10.1074/jbc.M103364200 | doi-access = free }} and progression of apoptosis. In interphase, cohesin may function in the control of gene expression by binding to numerous sites within the genome. As a structural component of the cohesin complex, RAD21 also contributes to various chromatin-associated functions, including DNA replication,{{cite journal | vauthors = Guillou E, Ibarra A, Coulon V, Casado-Vela J, Rico D, Casal I, Schwob E, Losada A, Méndez J | title = Cohesin organizes chromatin loops at DNA replication factories | journal = Genes & Development | volume = 24 | issue = 24 | pages = 2812–22 | date = December 2010 | pmid = 21159821 | pmc = 3003199 | doi = 10.1101/gad.608210 }}{{cite journal | vauthors = Takahashi TS, Yiu P, Chou MF, Gygi S, Walter JC | title = Recruitment of Xenopus Scc2 and cohesin to chromatin requires the pre-replication complex | journal = Nature Cell Biology | volume = 6 | issue = 10 | pages = 991–6 | date = October 2004 | pmid = 15448702 | doi = 10.1038/ncb1177 | url = http://www.nature.com/articles/ncb1177 | s2cid = 20488928 | url-access = subscription }}{{cite journal | vauthors = Ryu MJ, Kim BJ, Lee JW, Lee MW, Choi HK, Kim ST | title = Direct interaction between cohesin complex and DNA replication machinery | journal = Biochemical and Biophysical Research Communications | volume = 341 | issue = 3 | pages = 770–5 | date = March 2006 | pmid = 16438930 | doi = 10.1016/j.bbrc.2006.01.029 }}{{cite journal | vauthors = Terret ME, Sherwood R, Rahman S, Qin J, Jallepalli PV | title = Cohesin acetylation speeds the replication fork | journal = Nature | volume = 462 | issue = 7270 | pages = 231–4 | date = November 2009 | pmid = 19907496 | pmc = 2777716 | doi = 10.1038/nature08550 | bibcode = 2009Natur.462..231T }}{{cite journal | vauthors = MacAlpine HK, Gordân R, Powell SK, Hartemink AJ, MacAlpine DM | title = Drosophila ORC localizes to open chromatin and marks sites of cohesin complex loading | journal = Genome Research | volume = 20 | issue = 2 | pages = 201–11 | date = February 2010 | pmid = 19996087 | pmc = 2813476 | doi = 10.1101/gr.097873.109 }} DNA damage response (DDR),{{cite journal | vauthors = Unal E, Heidinger-Pauli JM, Koshland D | title = DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7) | journal = Science | volume = 317 | issue = 5835 | pages = 245–8 | date = July 2007 | pmid = 17626885 | doi = 10.1126/science.1140637 | bibcode = 2007Sci...317..245U | s2cid = 551399 }}{{cite journal | vauthors = Heidinger-Pauli JM, Unal E, Koshland D | title = Distinct targets of the Eco1 acetyltransferase modulate cohesion in S phase and in response to DNA damage | journal = Molecular Cell | volume = 34 | issue = 3 | pages = 311–21 | date = May 2009 | pmid = 19450529 | pmc = 2737744 | doi = 10.1016/j.molcel.2009.04.008 }}{{cite journal | vauthors = Ström L, Lindroos HB, Shirahige K, Sjögren C | title = Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair | journal = Molecular Cell | volume = 16 | issue = 6 | pages = 1003–15 | date = December 2004 | pmid = 15610742 | doi = 10.1016/j.molcel.2004.11.026 | doi-access = free }}{{cite journal | vauthors = Kim BJ, Li Y, Zhang J, Xi Y, Li Y, Yang T, Jung SY, Pan X, Chen R, Li W, Wang Y, Qin J | title = Genome-wide reinforcement of cohesin binding at pre-existing cohesin sites in response to ionizing radiation in human cells | journal = The Journal of Biological Chemistry | volume = 285 | issue = 30 | pages = 22784–92 | date = July 2010 | pmid = 20501661 | pmc = 2906269 | doi = 10.1074/jbc.M110.134577 | doi-access = free }}{{cite journal | vauthors = Watrin E, Peters JM | title = The cohesin complex is required for the DNA damage-induced G2/M checkpoint in mammalian cells | journal = The EMBO Journal | volume = 28 | issue = 17 | pages = 2625–35 | date = September 2009 | pmid = 19629043 | pmc = 2738698 | doi = 10.1038/emboj.2009.202 }}{{cite journal | vauthors = Cortés-Ledesma F, Aguilera A | title = Double-strand breaks arising by replication through a nick are repaired by cohesin-dependent sister-chromatid exchange | journal = EMBO Reports | volume = 7 | issue = 9 | pages = 919–26 | date = September 2006 | pmid = 16888651 | pmc = 1559660 | doi = 10.1038/sj.embor.7400774 }}{{cite journal | vauthors = Watrin E, Peters JM | title = Cohesin and DNA damage repair | journal = Experimental Cell Research | volume = 312 | issue = 14 | pages = 2687–93 | date = August 2006 | pmid = 16876157 | doi = 10.1016/j.yexcr.2006.06.024 }}{{cite journal | vauthors = Ball AR, Yokomori K | title = Damage-induced reactivation of cohesin in postreplicative DNA repair | journal = BioEssays | volume = 30 | issue = 1 | pages = 5–9 | date = January 2008 | pmid = 18081005 | pmc = 4127326 | doi = 10.1002/bies.20691 }}{{cite journal | vauthors = Sjögren C, Ström L | title = S-phase and DNA damage activated establishment of sister chromatid cohesion--importance for DNA repair | journal = Experimental Cell Research | volume = 316 | issue = 9 | pages = 1445–53 | date = May 2010 | pmid = 20043905 | doi = 10.1016/j.yexcr.2009.12.018 }} and most importantly, transcriptional regulation.{{cite journal | vauthors = Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, Tsutsumi S, Nagae G, Ishihara K, Mishiro T, Yahata K, Imamoto F, Aburatani H, Nakao M, Imamoto N, Maeshima K, Shirahige K, Peters JM | title = Cohesin mediates transcriptional insulation by CCCTC-binding factor | journal = Nature | volume = 451 | issue = 7180 | pages = 796–801 | date = February 2008 | pmid = 18235444 | doi = 10.1038/nature06634 | url = http://www.nature.com/articles/nature06634 | s2cid = 205212289 | bibcode = 2008Natur.451..796W | url-access = subscription }}{{cite journal | vauthors = Skibbens RV, Marzillier J, Eastman L | title = Cohesins coordinate gene transcriptions of related function within Saccharomyces cerevisiae | journal = Cell Cycle | volume = 9 | issue = 8 | pages = 1601–6 | date = April 2010 | pmid = 20404480 | pmc = 3096706 | doi = 10.4161/cc.9.8.11307 }}{{cite journal | vauthors = Schmidt D, Schwalie PC, Ross-Innes CS, Hurtado A, Brown GD, Carroll JS, Flicek P, Odom DT | title = A CTCF-independent role for cohesin in tissue-specific transcription | journal = Genome Research | volume = 20 | issue = 5 | pages = 578–88 | date = May 2010 | pmid = 20219941 | pmc = 2860160 | doi = 10.1101/gr.100479.109 }}{{cite journal | vauthors = Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA | title = Mediator and cohesin connect gene expression and chromatin architecture | journal = Nature | volume = 467 | issue = 7314 | pages = 430–5 | date = September 2010 | pmid = 20720539 | pmc = 2953795 | doi = 10.1038/nature09380 | bibcode = 2010Natur.467..430K }}{{cite journal | vauthors = Pauli A, van Bemmel JG, Oliveira RA, Itoh T, Shirahige K, van Steensel B, Nasmyth K | title = A direct role for cohesin in gene regulation and ecdysone response in Drosophila salivary glands | journal = Current Biology | volume = 20 | issue = 20 | pages = 1787–98 | date = October 2010 | pmid = 20933422 | pmc = 4763543 | doi = 10.1016/j.cub.2010.09.006 | bibcode = 2010CBio...20.1787P }}{{cite journal | vauthors = Dorsett D | title = Gene regulation: the cohesin ring connects developmental highways | journal = Current Biology | volume = 20 | issue = 20 | pages = R886-8 | date = October 2010 | pmid = 20971431 | doi = 10.1016/j.cub.2010.09.036 | s2cid = 2543711 | doi-access = free | bibcode = 2010CBio...20.R886D }}{{cite journal | vauthors = Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschlager M | title = Cohesins functionally associate with CTCF on mammalian chromosome arms | journal = Cell | volume = 132 | issue = 3 | pages = 422–33 | date = February 2008 | pmid = 18237772 | doi = 10.1016/j.cell.2008.01.011 | s2cid = 14363394 | doi-access = free }}{{cite journal | vauthors = Liu J, Zhang Z, Bando M, Itoh T, Deardorff MA, Clark D, Kaur M, Tandy S, Kondoh T, Rappaport E, Spinner NB, Vega H, Jackson LG, Shirahige K, Krantz ID | title = Transcriptional dysregulation in NIPBL and cohesin mutant human cells | journal = PLOS Biology | volume = 7 | issue = 5 | pages = e1000119 | date = May 2009 | pmid = 19468298 | pmc = 2680332 | doi = 10.1371/journal.pbio.1000119 | veditors = Hastie N | doi-access = free }}  Numerous recent functional and genomic studies have implicated chromosomal cohesin proteins as critical regulators of hematopoietic gene expression.{{cite journal | vauthors = Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, Corces MR, Flynn RA, Buenrostro JD, Chan SM, Thomas D, Koenig JL, Hong WJ, Chang HY, Majeti R | title = Leukemia-Associated Cohesin Mutants Dominantly Enforce Stem Cell Programs and Impair Human Hematopoietic Progenitor Differentiation | journal = Cell Stem Cell | volume = 17 | issue = 6 | pages = 675–688 | date = December 2015 | pmid = 26607380 | pmc = 4671831 | doi = 10.1016/j.stem.2015.09.017 }}{{cite journal 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Fisher JB, McNulty M, Burke MJ, Crispino JD, Rao S | title = Cohesin Mutations in Myeloid Malignancies | journal = Trends in Cancer | volume = 3 | issue = 4 | pages = 282–293 | date = April 2017 | pmid = 28626802 | pmc = 5472227 | doi = 10.1016/j.trecan.2017.02.006 }}{{cite journal | vauthors = Rao S | title = Closing the loop on cohesin in hematopoiesis | journal = Blood | volume = 134 | issue = 24 | pages = 2123–2125 | date = December 2019 | pmid = 31830276 | pmc = 6908834 | doi = 10.1182/blood.2019003279 }}

As a part of cohesin complex, functions of Rad21 in the regulation of gene expression include: 1) allele-specific transcription by interacting with the boundary element CCCTC-binding factor (CTCF),{{cite journal | vauthors = Degner SC, Verma-Gaur J, Wong TP, Bossen C, Iverson GM, Torkamani A, Vettermann C, Lin YC, Ju Z, Schulz D, Murre CS, Birshtein BK, Schork NJ, Schlissel MS, Riblet R, Murre C, Feeney AJ | title = CCCTC-binding factor (CTCF) and cohesin influence the genomic architecture of the Igh locus and antisense transcription in pro-B cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 23 | pages = 9566–71 | date = June 2011 | pmid = 21606361 | pmc = 3111298 | doi = 10.1073/pnas.1019391108 | bibcode = 2011PNAS..108.9566D | doi-access = free }}{{cite journal | vauthors = Guo Y, Monahan K, Wu H, Gertz J, Varley KE, Li W, Myers RM, Maniatis T, Wu Q | title = CTCF/cohesin-mediated DNA looping is required for protocadherin α promoter choice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 51 | pages = 21081–6 | date = December 2012 | pmid = 23204437 | pmc = 3529044 | doi = 10.1073/pnas.1219280110 | bibcode = 2012PNAS..10921081G | doi-access = free }} 2) tissue-specific transcription by interacting with tissue-specific transcription factors,{{cite journal | vauthors = Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, Merkenschlager M | title = Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus | journal = Nature | volume = 460 | issue = 7253 | pages = 410–3 | date = July 2009 | pmid = 19458616 | pmc = 2869028 | doi = 10.1038/nature08079 | bibcode = 2009Natur.460..410H }}{{cite journal | vauthors = Faure AJ, Schmidt D, Watt S, Schwalie PC, Wilson MD, Xu H, Ramsay RG, Odom DT, Flicek P | title = Cohesin regulates tissue-specific expression by stabilizing highly occupied cis-regulatory modules | journal = Genome Research | volume = 22 | issue = 11 | pages = 2163–75 | date = November 2012 | pmid = 22780989 | pmc = 3483546 | doi = 10.1101/gr.136507.111 }}{{cite journal | vauthors = Seitan VC, Hao B, Tachibana-Konwalski K, Lavagnolli T, Mira-Bontenbal H, Brown KE, Teng G, Carroll T, Terry A, Horan K, Marks H, Adams DJ, Schatz DG, Aragon L, Fisher AG, Krangel MS, Nasmyth K, Merkenschlager M | title = A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation | journal = Nature | volume = 476 | issue = 7361 | pages = 467–71 | date = August 2011 | pmid = 21832993 | pmc = 3179485 | doi = 10.1038/nature10312 | bibcode = 2011Natur.476..467S }}{{cite journal | vauthors = Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, Schmierer B, Jolma A, Kivioja T, Taipale M, Taipale J | title = Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites | journal = Cell | volume = 154 | issue = 4 | pages = 801–13 | date = August 2013 | pmid = 23953112 | doi = 10.1016/j.cell.2013.07.034 | doi-access = free }}{{cite journal | vauthors = Zhang H, Jiao W, Sun L, Fan J, Chen M, Wang H, Xu X, Shen A, Li T, Niu B, Ge S, Li W, Cui J, Wang G, Sun J, Fan X, Hu X, Mrsny RJ, Hoffman AR, Hu JF | title = Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming | journal = Cell Stem Cell | volume = 13 | issue = 1 | pages = 30–5 | date = July 2013 | pmid = 23747202 | doi = 10.1016/j.stem.2013.05.012 | doi-access = free }} 3) general progression of transcription by communicating with the basal transcription machinery,{{cite journal | vauthors = Fay A, Misulovin Z, Li J, Schaaf CA, Gause M, Gilmour DS, Dorsett D | title = Cohesin selectively binds and regulates genes with paused RNA polymerase | journal = Current Biology | volume = 21 | issue = 19 | pages = 1624–34 | date = October 2011 | pmid = 21962715 | pmc = 3193539 | doi = 10.1016/j.cub.2011.08.036 | bibcode = 2011CBio...21.1624F }}{{cite journal | vauthors = Schaaf CA, Kwak H, Koenig A, Misulovin Z, Gohara DW, Watson A, Zhou Y, Lis JT, Dorsett D | title = Genome-wide control of RNA polymerase II activity by cohesin | journal = PLOS Genetics | volume = 9 | issue = 3 | pages = e1003382 | date = March 2013 | pmid = 23555293 | pmc = 3605059 | doi = 10.1371/journal.pgen.1003382 | veditors = Ren B | doi-access = free }} and 4) RAD21 co-localization with CTCF-independent pluripotency factors (Oct4, Nanog, Sox4, and KLF2). RAD21 cooperates with CTCF,{{cite journal | vauthors = Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, Aebersold R, Ranish JA, Krumm A | title = CTCF physically links cohesin to chromatin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 24 | pages = 8309–14 | date = June 2008 | pmid = 18550811 | pmc = 2448833 | doi = 10.1073/pnas.0801273105 | bibcode = 2008PNAS..105.8309R | doi-access = free }} tissue-specific transcription factors, and basal transcription machinery to regulate transcription dynamically.{{cite journal | vauthors = Dorsett D, Merkenschlager M | title = Cohesin at active genes: a unifying theme for cohesin and gene expression from model organisms to humans | journal = Current Opinion in Cell Biology | volume = 25 | issue = 3 | pages = 327–33 | date = June 2013 | pmid = 23465542 | pmc = 3691354 | doi = 10.1016/j.ceb.2013.02.003 }} Also, to effectuate proper transcription activation, cohesin loops chromatin to bring two distant regions together. Cohesin may also act as a transcription insulator to ensure repression. Thus, RAD21 can affect both activation and repression of transcription.  Enhancers that promote transcription and insulators that block transcription are located in conserved regulatory elements (CREs) on chromosomes, and cohesins are thought to physically connect distant CREs with gene promoters in a cell-type specific manner to modulate transcriptional outcome.{{cite journal | vauthors = Leeke B, Marsman J, O'Sullivan JM, Horsfield JA | title = Cohesin mutations in myeloid malignancies: underlying mechanisms | journal = Experimental Hematology & Oncology | volume = 3 | issue = 1 | pages = 13 | date = 2014 | pmid = 24904756 | pmc = 4046106 | doi = 10.1186/2162-3619-3-13 | doi-access = free }}

In meiosis, REC8 is expressed and replaces RAD21 in the cohesin complex. REC8-containing cohesin generates cohesion between homologous chromosomes and sister chromatids which can persist for years in the case of mammalian oocytes.{{cite journal | vauthors = Tachibana-Konwalski K, Godwin J, van der Weyden L, Champion L, Kudo NR, Adams DJ, Nasmyth K | title = Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes | journal = Genes & Development | volume = 24 | issue = 22 | pages = 2505–16 | date = November 2010 | pmid = 20971813 | pmc = 2975927 | doi = 10.1101/gad.605910 }}{{cite journal | vauthors = Buonomo SB, Clyne RK, Fuchs J, Loidl J, Uhlmann F, Nasmyth K | title = Disjunction of homologous chromosomes in meiosis I depends on proteolytic cleavage of the meiotic cohesin Rec8 by separin | journal = Cell | volume = 103 | issue = 3 | pages = 387–98 | date = October 2000 | pmid = 11081626 | doi = 10.1016/S0092-8674(00)00131-8 | s2cid = 17385055 | doi-access = free }} RAD21L is a further paralog of RAD21 that has a role in meiotic chromosome segregation.{{cite journal | vauthors = Lee J, Hirano T | title = RAD21L, a novel cohesin subunit implicated in linking homologous chromosomes in mammalian meiosis | journal = The Journal of Cell Biology | volume = 192 | issue = 2 | pages = 263–76 | date = January 2011 | pmid = 21242291 | pmc = 3172173 | doi = 10.1083/jcb.201008005 }}  The major role of Rad21L cohesin complex is in homologue pairing and synapsis, not in sister chromatid cohesion, whereas Rec8 most likely functions in sister chromatid cohesion.  Intriguingly, concomitantly with the disappearance of RAD21L, Rad21 appears on the chromosomes in late pachytene and mostly dissociates after diplotene onward.{{cite journal | vauthors = Ishiguro K, Kim J, Fujiyama-Nakamura S, Kato S, Watanabe Y | title = A new meiosis-specific cohesin complex implicated in the cohesin code for homologous pairing | journal = EMBO Reports | volume = 12 | issue = 3 | pages = 267–75 | date = March 2011 | pmid = 21274006 | pmc = 3059921 | doi = 10.1038/embor.2011.2 }} The function of Rad21 cohesin that transiently appears in late prophase I is unclear.

Germline heterozygous or homozygous missense mutations in RAD21 have been associated with human genetic disorders, including developmental diseases such as Cornelia de Lange syndrome{{cite journal | vauthors = Krab LC, Marcos-Alcalde I, Assaf M, Balasubramanian M, Andersen JB, Bisgaard AM, Fitzpatrick DR, Gudmundsson S, Huisman SA, Kalayci T, Maas SM, Martinez F, McKee S, Menke LA, Mulder PA, Murch OD, Parker M, Pie J, Ramos FJ, Rieubland C, Rosenfeld Mokry JA, Scarano E, Shinawi M, Gómez-Puertas P, Tümer Z, Hennekam RC | title = Delineation of phenotypes and genotypes related to cohesin structural protein RAD21 | journal = Human Genetics | volume = 139 | issue = 5 | pages = 575–592 | date = May 2020 | pmid = 32193685 | pmc = 7170815 | doi = 10.1007/s00439-020-02138-2 }}{{cite journal | vauthors = Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Mönnich M, Yan Y, Xu W, Gil-Rodríguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, Van Maldergem L, Lynch SA, Gillessen-Kaesbach G, Lüdecke HJ, Ramsay RG, McKay MJ, Krantz ID, Xu H, Horsfield JA, Kaiser FJ | title = RAD21 mutations cause a human cohesinopathy | journal = American Journal of Human Genetics | volume = 90 | issue = 6 | pages = 1014–27 | date = June 2012 | pmid = 22633399 | pmc = 3370273 | doi = 10.1016/j.ajhg.2012.04.019 }}{{cite journal | vauthors = Ansari M, Poke G, Ferry Q, Williamson K, Aldridge R, Meynert AM, Bengani H, Chan CY, Kayserili H, Avci S, Hennekam RC, Lampe AK, Redeker E, Homfray T, Ross A, Falkenberg Smeland M, Mansour S, Parker MJ, Cook JA, Splitt M, Fisher RB, Fryer A, Magee AC, Wilkie A, Barnicoat A, Brady AF, Cooper NS, Mercer C, Deshpande C, Bennett CP, Pilz DT, Ruddy D, Cilliers D, Johnson DS, Josifova D, Rosser E, Thompson EM, Wakeling E, Kinning E, Stewart F, Flinter F, Girisha KM, Cox H, Firth HV, Kingston H, Wee JS, Hurst JA, Clayton-Smith J, Tolmie J, Vogt J, Tatton-Brown K, Chandler K, Prescott K, Wilson L, Behnam M, McEntagart M, Davidson R, Lynch SA, Sisodiya S, Mehta SG, McKee SA, Mohammed S, Holden S, Park SM, Holder SE, Harrison V, McConnell V, Lam WK, Green AJ, Donnai D, Bitner-Glindzicz M, Donnelly DE, Nellåker C, Taylor MS, FitzPatrick DR | title = Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism | journal = Journal of Medical Genetics | volume = 51 | issue = 10 | pages = 659–68 | date = October 2014 | pmid = 25125236 | pmc = 4173748 | doi = 10.1136/jmedgenet-2014-102573 }}{{cite journal | vauthors = Minor A, Shinawi M, Hogue JS, Vineyard M, Hamlin DR, Tan C, Donato K, Wysinger L, Botes S, Das S, Del Gaudio D | title = Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case | journal = Gene | volume = 537 | issue = 2 | pages = 279–84 | date = March 2014 | pmid = 24378232 | doi = 10.1016/j.gene.2013.12.045 }}{{cite journal | vauthors = Boyle MI, Jespersgaard C, Nazaryan L, Bisgaard AM, Tümer Z | title = A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome - review of the literature | journal = Clinical Genetics | volume = 91 | issue = 4 | pages = 647–649 | date = April 2017 | pmid = 27882533 | doi = 10.1111/cge.12863 | s2cid = 3732288 }}{{cite journal | vauthors = Martínez F, Caro-Llopis A, Roselló M, Oltra S, Mayo S, Monfort S, Orellana C | title = High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing | journal = Journal of Medical Genetics | volume = 54 | issue = 2 | pages = 87–92 | date = February 2017 | pmid = 27620904 | doi = 10.1136/jmedgenet-2016-103964 | s2cid = 46740644 }}{{cite journal | vauthors = Dorval S, Masciadri M, Mathot M, Russo S, Revencu N, Larizza L | title = A novel RAD21 mutation in a boy with mild Cornelia de Lange presentation: Further delineation of the phenotype | journal = European Journal of Medical Genetics | volume = 63 | issue = 1 | pages = 103620 | date = January 2020 | pmid = 30716475 | doi = 10.1016/j.ejmg.2019.01.010 | s2cid = 73443712 | doi-access = | hdl = 2078.1/213923 | hdl-access = free }}{{cite journal | vauthors = Gudmundsson S, Annerén G, Marcos-Alcalde Í, Wilbe M, Melin M, Gómez-Puertas P, Bondeson ML | title = A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4 - Review of the literature | journal = European Journal of Medical Genetics | volume = 62 | issue = 6 | pages = 103526 | date = June 2019 | pmid = 30125677 | doi = 10.1016/j.ejmg.2018.08.007 | hdl = 10641/1986 | s2cid = 52046223 | hdl-access = free }}{{cite journal | vauthors = Pereza N, Severinski S, Ostojić S, Volk M, Maver A, Dekanić KB, Kapović M, Peterlin B | title = Cornelia de Lange syndrome caused by heterozygous deletions of chromosome 8q24: comments on the article by Pereza et al. 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Part A | volume = 146A | issue = 12 | pages = 1587–92 | date = June 2008 | pmid = 18478595 | doi = 10.1002/ajmg.a.32347 | s2cid = 19384557 }} and chronic intestinal pseudo-obstruction called Mungan syndrome,{{cite journal | vauthors = Bonora E, Bianco F, Cordeddu L, Bamshad M, Francescatto L, Dowless D, Stanghellini V, Cogliandro RF, Lindberg G, Mungan Z, Cefle K, Ozcelik T, Palanduz S, Ozturk S, Gedikbasi A, Gori A, Pippucci T, Graziano C, Volta U, Caio G, Barbara G, D'Amato M, Seri M, Katsanis N, Romeo G, De Giorgio R | title = Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction | journal = Gastroenterology | volume = 148 | issue = 4 | pages = 771–782.e11 | date = April 2015 | pmid = 25575569 | pmc = 4375026 | doi = 10.1053/j.gastro.2014.12.034 | hdl = 11693/23636 }}{{cite journal | vauthors = Mungan Z, Akyüz F, Bugra Z, Yönall O, Oztürk S, Acar A, Cevikbas U | title = Familial visceral myopathy with pseudo-obstruction, megaduodenum, 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