title: SATB1 cleavage by caspase 6 disrupts PDZ domain-mediated dimerization, causing detachment from chromatin early in T-cell apoptosis.
abstract: SATB1 is expressed primarily in thymocytes and orchestrates temporal and spatial expression of a large number of genes in the T-cell lineage. SATB1 binds to the bases of chromatin loop domains in vivo, recognizing a special DNA context with strong base-unpairing propensity. The majority of thymocytes 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 that this cleavage separates the DNA-binding domains from amino acids 90 to 204, a region which we show to be a dimerization domain. The resulting SATB1 monomer loses its BUR-binding activity, despite containing both its DNA-binding domains, and rapidly dissociates from chromatin in vivo. We found this dimerization region to have sequence similarity to PDZ domains, which have been previously shown to be involved in signaling by conferring protein-protein 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 ~50-kb fragments. Our results suggest that mechanisms of nuclear degradation early in apoptotic T cells involve efficient removal of SATB1 by disrupting its dimerization and cleavage of genomic DNA into loop domains to ensure rapid and efficient disassembly of higher-order chromatin structure.
authors.affiliation: Department of Cell and Molecular Biology, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Galande
authors.forename: L A
authors.initials: LA
authors.lastname: Dickinson
authors.forename: I S
authors.initials: IS
authors.lastname: Mian
authors.forename: M
authors.initials: M
authors.lastname: Sikorska
authors.forename: T
authors.initials: T
authors.lastname: Kohwi-Shigematsu
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology*; D053178:Caspase 6; D020169:Caspases / Q000502:physiology*; D002843:Chromatin / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D019169:Jurkat Cells; D036961:Matrix Attachment Region Binding Proteins; D008969:Molecular Sequence Data; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology*
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D036961:Matrix Attachment Region Binding Proteins; C076189:SATB1 protein, human; C505514:CASP6 protein, human; D053178:Caspase 6; D020169:Caspases