ATR-X Syndrome Protein Targets Tandem Repeats and Influences Allele-Specific Expression in a Size-Dependent Manner
ATR-X Syndrome Protein Targets Tandem Repeats and Influences Allele-Specific Expression in a Size-Dependent Manner
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DOI：
10.1016/j.cell.2010.09.023
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发表时间：
2010-10-29
期刊：
影响因子：
64.5
通讯作者：
Gibbons, Richard J.
中科院分区：
文献类型：
--
作者：
Law, Martin J.;Lower, Karen M.;Gibbons, Richard J.
ATRX 是 SWI/SNF 家族的 X 连锁基因，其突变会导致综合征性智力低下和 a-珠蛋白表达下调。在这里，我们证明 ATRX 与端粒和常染色质中的串联重复 (TR) 序列结合。当 ATRX 突变时，与这些 TR 相关的基因可能会失调，并且表达的变化由 TR 的大小决定，从而产生倾斜的等位基因表达。这揭示了受影响基因的特征，解释了相同 ATRX 突变所见的可变表型，并说明了可变外显率背后的新机制。许多 TR 富含 G，预计会在体内形成非 B DNA 结构（包括 G 四联体）。我们证明 ATRX 在体外结合 G-四链体结构，表明 ATRX 在各种核过程中发挥作用的机制以及当 ATRX 突变时该机制如何受到干扰。
ATRX is an X-linked gene of the SWI/SNF family, mutations in which cause syndromal mental retardation and downregulation of a-globin expression. Here we show that ATRX binds to tandem repeat (TR) sequences in both telomeres and euchromatin. Genes associated with these TRs can be 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. Many of the TRs are G rich and predicted to form non-B DNA structures (including G-quadruplex) in vivo. We show that ATRX binds G-quadruplex structures in vitro, suggesting a mechanism by which ATRX may play a role in various nuclear processes and how this is perturbed when ATRX is mutated.