The ATRX Syndrome Protein Forms a Chromatin-Remodeling Complex with Daxx and Localizes in Promyelocytic Leukemia Nuclear Bodies

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-09, Vol.100 (19), p.10635-10640
• Main Authors: Xue, Yutong, Gibbons, Richard, Yan, Zhijiang, Yang, Dafeng, McDowell, Tarra L., Sechi, Salvatore, Qin, Jun, Zhou, Sharleen, Higgs, Doug, Wang, Weidong
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adenosine triphosphatases; Adenosine Triphosphate - metabolism; Biochemistry; Biological Sciences; Carrier Proteins - metabolism; Cell lines; Cell Nucleus - metabolism; Chromatin; Chromatin - metabolism; DNA; DNA Helicases - metabolism; Eukaryotes; Fluorescent Antibody Technique; Fractionation; Gene expression; HeLa cells; Humans; Immunoprecipitation; Intracellular Signaling Peptides and Proteins; Leukemia; Leukemia, Promyelocytic, Acute - metabolism; Nuclear Proteins - metabolism; Nucleosomes; Nucleotides; Proteins; Renovations; X-linked Nuclear Protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1937626100

ATRX syndrome is characterized by X-linked mental retardation associated with α-thalassemia. The gene mutated in this disease, ATRX, encodes a plant homeodomain-like finger and a SWI2/SNF2-like ATPase motif, both of which are often found in chromatin-remodeling enzymes, but ATRX has not been characterized biochemically. By immunoprecipitation from HeLa extract, we found that ATRX is in a complex with transcription cofactor Daxx. The following evidence supports that ATRX and Daxx are components of an ATP-dependent chromatin-remodeling complex: (i) Daxx and ATRX can be coimmunoisolated by antibodies specific for each protein; (ii) a proportion of Daxx cofractionates with ATRX as a complex of 1 MDa by gel-filtration analysis; (iii) in extract from cells of a patient with ATRX syndrome, the level of the Daxx-ATRX complex is correspondingly reduced; (iv) a proportion of ATRX and Daxx colocalize in promyelocytic leukemia nuclear bodies, with which Daxx had previously been located; and (v) the ATRX complex displays ATP-dependent activities that resemble those of other chromatin-remodeling complexes, including triple-helix DNA displacement and alteration of mononucleosome disruption patterns. But unlike the previously described SWI/SNF or NURD complexes, the ATRX complex does not randomize DNA phasing of the mononucleosomes, suggesting that it may remodel chromatin differently. Taken together, the results suggest that ATRX functions in conjunction with Daxx in a novel chromatin-remodeling complex. The defects in ATRX syndrome may result from inappropriate expression of genes controlled by this complex.