ATR-X Syndrome Protein Targets Tandem Repeats and Influences Allele-Specific Expression in a Size-Dependent Manner

Summary ATRXis an X-linked gene of the SWI/SNFfamily, mutations in which cause syndromal mental retardation and downregulation of α-globin expression. Here we show that ATRXbinds to tandem repeat(TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be dysregulated when ATRXis mutated, and the change in expression is determined by the size of the TR, producing skewed allelic expression. This reveals the characteristics of the affected genes, explains the variable phenotypes seen with identical ATRXmutations, and illustrates a new mechanism underlying variable penetrance. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRXbinds G-quadruplexstructures in vitro, suggesting a mechanism by which ATRXmay play a role in various nuclear processes and how this is perturbed when ATRXis mutated. PaperClip