Abstract
The mixed lineage leukemia protein MLL1 contains four highly conserved plant 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.
Highlights
MLL1 contains four plant homeodomain (PHD) fingers that are deleted in leukemogenic MLL1 fusion proteins
As several PHD fingers function as E3 ligases, we investigated whether any of the MLL1 PHD fingers have this activity
No ubiquitination activity was observed with the mutant, indicating that the observed E3 ubiquitin ligase activity is intrinsic to PHD2 (Fig. 1C)
Summary
MLL1 contains four PHD fingers that are deleted in leukemogenic MLL1 fusion proteins. The function of PHD fingers has been under intensive study due to their close association with various diseases These studies have revealed that this domain has multiple functions, including recognition of different histone marks, DNA binding, and mediation of protein-protein interactions [16, 17]. We discovered that the second PHD finger of MLL1 has intrinsic E3 ligase activity that is conserved in at least one other closely related MLL family member, MLL4. This activity requires the E2-conjugating enzyme CDC34, which interacts with MLL1 in vitro and in vivo. MLL1 is associated with increased transactivation ability and MLL1 recruitment to target gene promoters
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