ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome

Abstract

ATR-X (alpha thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the patient missense mutations are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, AD-DATRX), indicating its importance. However, the function of ADDATRX has remained elusive. Here we identify ADDATRX as a novel histone H3 binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by H3K4me3. The co-crystal structures of ADDATRX bound to H31–15K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Importantly, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin. Thus, we have discovered a unique histone recognition mechanism underlying the ATR-X etiology.