Regulation of trypanosome DNA glycosylation by a SWI2/SNF2-like protein

Synthesis of the modified thymine base beta-D-glucosyl-hydroxymethyluracil, or J, within telomeric DNA of Trypanosoma brucei correlates with the bloodstream-form-specific epigenetic silencing of telomeric variant surface glycoprotein genes involved in antigenic variation. The mechanism of developmental and telomeric-specific regulation of J synthesis is unknown. We have previously identified a J binding protein (JBP1) involved in propagating J synthesis. We have now identified a homolog of JBP1, JBP2, containing a domain related to the SWI2/SNF2 family of chromatin remodeling proteins that is upregulated in bloodstream form cells and interacts with nuclear chromatin. We show that expression of JBP2 in procyclic form cells leads to de novo J synthesis within telomeric regions of the chromosome and that this activity is inhibited after mutagenesis of conserved residues critical for SWI2/SNF2 function. We propose a model in which chromatin remodeling by JBP2 regulates the initial sites of J synthesis within bloodstream form trypanosome DNA, with further propagation and maintenance of J by JBP1.     

SWI/SNF complex in disorder

Heterozygous germline mutations in components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes were recently identified in patients with non-syndromic intellectual disability, Coffin-Siris syndrome and Nicolaides-Baraitser syndrome. The common denominator of the phenotype of these patients is severe intellectual disability and speech delay. Somatic and germline mutations in SWI/SNF components were previously implicated in tumor development. This raises the question whether patients with intellectual disability caused by SWI/SNF mutations in the germline are exposed to an increased risk of developing cancer. Here we compare the mutational spectrum of SWI/SNF components in intellectual disability syndromes and cancer, and discuss the implications of the results of this comparison for the patients.