Linder B, Newman R, Jones L K, Debernardi S, Young B D, Freemont P, Verrijzer C P, Saha V
Department of Medical Oncology, St Bartholomew's and the Royal London Hospital School of Medicine, Imperial Cancer Research Fund, Charterhouse Square, London, EC1 M 6BQ, England.
J Mol Biol. 2000 Jun 2;299(2):369-78. doi: 10.1006/jmbi.2000.3766.
Leukaemogenesis correlates with alterations in chromatin structure brought about by the gain or loss of interactive domains from regulatory factors that are disrupted by chromosomal translocations. The gene MLL, a target of such translocation events, forms chimaeric fusion products with a variety of partner genes. While MLL appears to be involved in chromatin-mediated gene regulation, the functions of its partner genes are largely speculative. We report the biochemical analysis of the MLL partner gene AF10 and its possible role in leukaemogenesis. AF10 has been reported to be re-arranged with genes other than MLL leading to the same phenotype, a myeloid leukaemia. We have identified a novel protein-protein interaction motif in the AF10 protein comprising the extended LAP/PHD-finger. This domain mediates homo-oligomerisation of recombinant AF10 and is conserved in several proteins, including MLL itself. AF10 binds cruciform DNA via a specific interaction with an AT-hook motif and is localised to the nucleus by a defined bipartite nuclear localisation signal in the N-terminal region.
白血病发生与染色质结构改变相关，这种改变是由染色体易位破坏的调节因子的相互作用结构域的增减所引起的。基因MLL是此类易位事件的一个靶点，它与多种伙伴基因形成嵌合融合产物。虽然MLL似乎参与染色质介导的基因调控，但其伙伴基因的功能大多是推测性的。我们报告了对MLL伙伴基因AF10的生化分析及其在白血病发生中的可能作用。据报道，AF10与MLL以外的基因重排会导致相同的表型，即髓系白血病。我们在AF10蛋白中鉴定出一个新的蛋白质-蛋白质相互作用基序，它由延伸的LAP/PHD指组成。该结构域介导重组AF10的同源寡聚化，并且在包括MLL自身在内的几种蛋白质中保守。AF10通过与一个AT钩基序的特异性相互作用结合十字形DNA，并通过N端区域中一个明确的双分型核定位信号定位于细胞核。
