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New insights into the role of the chromatin associated factor ATRX

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ATRX is an X-linked gene of the SWI /SNF family, mutations in which cause syndromal mental retardation and downregulation of alpha-globin expression. We have shown that ATRX binds to tandem repeat (TR) sequences in both telomeres and pericentromeric chromosomal regions where ATRX may be targeted by recognizing specific chromatin modifications. Within euchromatin ATRX is also associated with TRs associated with a subset of genes, some of which are dysregulated when ATRX is 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 ATRX mutations, and illustrates a new mechanism underlying variable penetrance in human genetic disease. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We have shown that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes including telomere biology and how this is perturbed when ATRX is mutated.

This talk is part of the MRC LMB Seminar Series series.

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