A Subset of Mixed Lineage Leukemia Proteins Has Plant Homeodomain (PHD)-mediated E3 Ligase Activity

Jingya Wang, Andrew G. Muntean, Laura Wu, Jay L. Hess
2012 Journal of Biological Chemistry  
MLL1 contains four PHD fingers that are deleted in leukemogenic MLL1 fusion proteins. Results: The second PHD finger of MLL1 exhibits E3 ubiquitin ligase activity, and this activity is conserved in MLL4. Conclusion: PHD2 ligase activity potentially regulates MLL1 levels and activity. Significance: This study reveals a novel activity of MLL PHD fingers that may have important roles in gene regulation and carcinogenesis. The mixed lineage leukemia protein MLL1 contains four highly conserved plant
more » ... homeodomain (PHD) fingers, which are invariably deleted in oncogenic MLL1 fusion proteins in human leukemia. Here we show that the second PHD finger (PHD2) of MLL1 is an E3 ubiquitin ligase in the presence of the E2-conjugating enzyme CDC34. This activity is conserved in the second PHD finger of MLL4, the closest homolog to MLL1 but not in MLL2 or MLL3. Mutation of PHD2 leads to MLL1 stabilization, as well as increased transactivation ability and MLL1 recruitment to the target gene loci, suggesting that PHD2 negatively regulates MLL1 activity. . 2 The abbreviations used are: MLL1, mixed lineage leukemia protein; PHD, plant homeodomain; MBP, myelin basic protein; qPCR, quantitative PCR; LUC, luciferase.
doi:10.1074/jbc.m112.423855 pmid:23129768 pmcid:PMC3527928 fatcat:yt47l7f7wvgpnoc2tsoqdvsck4