cohesion and congression. The 280-kD protein includes an unusual N-terminal PHD designated the ATRX-DNMT3-DNMT3L (ADD) domain, owing to its similarity to a protein region found in the DNA methyltransferases (DNMTs). However, the relationship of this domain to its role in DNA methylation is unclear. Remarkably, in several tumors, notably glioma, it is mutated along with DAXX and histone H3.3, identifying a genetic pathway contributing to these tumors (103). Patients with somatic null mutations in ATRX do not have a predisposition to cancer (102), indicating that other genes must contribute to the pathogenesis of cancer in those cases. Almost certainly, these genes are DAXX and H3.3. ATRX is located in the heterochromatin, and null mutations in SUV39H1 and SUV39H2, which place the H3K9Me3 mark, prevent its localization to the heterochromatin (104). Although human genetics strongly implicate a pathway contributing to cancer, the role of defective H3.3 placement in cancer is still unclear.
