ATRX syndrome represents a combination of alpha-thalassemia, mental retardation, and multiple associated developmental abnormalities. The gene defective in ATRX has been localized to the X chromosome and cloned. Mutations in the same gene also cause several other forms of syndromal X-linked mental retardation. The ATRX gene encodes a gene product containing a SWI2/SNF2-type DNA-dependent ATPase domain. Thus, it has been hypothesized that ATRX could function in an ATP-dependent chromatin-remodeling complex and participate in regulation of gene expression. We established a collaboration with Drs. Doug Higgs and Richard Gibbons, who had cloned the ATRX gene, and have discovered important features of its function. By immunoprecipitation from HeLa extract, we found that 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: 1) Daxx and ATRX can be coimmunoisolated by antibodies specific for each protein; 2) a proportion of Daxx co-fractionates with ATRX as a complex of 1 MDa by gelfiltration analysis; 3) in extract from cells of a patient with ATRX syndrome, the level of the Daxx-ATRX complex is correspondingly reduced; 4) a proportion of ATRX and Daxx colocalize in PML nuclear bodies, with which Daxx had previously been located; and 5) 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 ATR-X syndrome may result from inappropriate expression of genes controlled by this complex.
| Xue, Yutong; Gibbons, Richard; Yan, Zhijiang et al. (2003) The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. Proc Natl Acad Sci U S A 100:10635-40 |
