SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis

SATB1 is expressed primarily in thymocytes and orchestrates temporal and sp atial expression of a large number of genes in the T-cell lineage. SATB1 bi nds to the bases of chromatin loop domains in vivo, recognizing a special D NA context with strong base-unpairing propensity. The majority of thymocyte s are eliminated by apoptosis due to selection processes in the thymus. We investigated the fate of SATB1 during thymocyte and T-cell apoptosis. Here we show that SATB1 is specifically cleaved by a caspase 6-like protease at amino acid position 254 to produce a 65-kDa major fragment containing both a base-unpairing region (BUR)-binding domain and a homeodomain. We found th at this cleavage separates the DNA-binding domains from amino acids 90 to 2 04, a region which we show to be a dimerization domain. The resulting SATB1 monomer loses its BUR-binding activity, despite containing both its DNA-bi nding domains, and rapidly dissociates from chromatin in vivo. We found thi s dimerization region to have sequence similarity to PDZ domains, which hav e been previously shown to be involved in signaling by conferring protein-p rotein interactions. SATB1 cleavage during Jurkat T-cell apoptosis induced by an anti-Fas antibody occurs concomitantly with the high-molecular-weight fragmentation of chromatin of similar to 50-kb fragments. Our results sugg est that mechanisms of nuclear degradation early in apoptotic T cells invol ve efficient removal of SATB1 by disrupting its dimerization and cleavage o f genomic DNA into loop domains to ensure rapid and efficient disassembly o f higher-order chromatin structure.