RAD21

RAD21 (SCC1, hHR21, NXP-1) is the alpha-kleisin subunit of the human cohesin complex. Its N-terminal domain binds the ATPase head of SMC3 and its C-terminal winged-helix domain binds the ATPase head of SMC1A, so that RAD21 bridges the two SMC heads and closes the tripartite SMC1A-SMC3-RAD21 ring; its central region is the docking platform for the HEAT-repeat subunit STAG1 or STAG2 and, through STAG, for the regulators PDS5A/PDS5B, WAPL and the loader NIPBL-MAU2. RAD21 has no catalytic activity; ATP binding and hydrolysis are performed by the SMC heads. RAD21-containing cohesin is loaded onto chromatin by NIPBL-MAU2 in telophase/G1, is converted during DNA replication (ESCO1/2 acetylation of SMC3, sororin binding) into a stably bound, cohesive form, and topologically entraps the two sister chromatids so that they remain paired from S phase until anaphase, which is required for chromosome biorientation and accurate mitotic segregation. In prophase most arm cohesin is released without cleavage by the WAPL pathway, promoted by PLK1 phosphorylation of STAG2 and CDK1 phosphorylation of sororin, whereas centromeric cohesin is protected by SGO1-PP2A. At anaphase onset separase (ESPL1) cleaves RAD21 after Arg172 and Arg450, opening the ring and triggering sister chromatid separation; RAD21 cleavage is essential for anaphase and for completion of cytokinesis, and PLK1-dependent phosphorylation of RAD21 enhances its cleavability. The cleaved fragments are cleared from recycled cohesin after HDAC8 deacetylation of SMC3. In interphase, RAD21-containing cohesin also extrudes chromatin loops that are anchored at convergent CTCF sites, building topologically associating domains and enhancer-promoter contacts; through this it acts as a transcriptional insulator and regulator (for example at H19/IGF2 and MYC), and cohesin-STAG2 additionally mediates CTCF-independent enhancer-promoter contacts. Cohesin accumulates at DNA double-strand breaks, facilitates recombinational repair using the sister chromatid, is SUMOylated during repair, and is required for the DNA damage-induced intra-S and G2/M checkpoints. RAD21 is hyperphosphorylated in mitosis and is cleaved after Asp279 by caspase-3/-7 early in apoptosis, generating a 64-kDa C-terminal fragment that relocates to the cytoplasm and amplifies the death signal. It is nuclear throughout interphase, lies along chromosome arms and is enriched at centromeres of metaphase chromosomes, is recovered in nuclear-matrix fractions and, as soluble mitotic cohesin, has been reported at spindle poles in association with NuMA. Heterozygous loss-of-function RAD21 variants cause Cornelia de Lange syndrome type 4 and biallelic variants cause Mungan syndrome (visceral neuromyopathy); altered RAD21 dosage reshapes three-dimensional genome organisation and transcription in cancer.

Disorders

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