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

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.     

E2F1 mediates DNA damage and apoptosis through HCF‐1 and the MLL family of histone methyltransferases

E2F1 is a key positive regulator of human cell proliferation and its activity is altered in essentially all human cancers. Deregulation of E2F1 leads to oncogenic DNA damage and anti‐oncogenic apoptosis. The molecular mechanisms by which E2F1 mediates these two processes are poorly understood but are important for understanding cancer progression. During the G1‐to‐S phase transition, E2F1 associates through a short DHQY sequence with the cell‐cycle regulator HCF‐1 together with the mixed‐lineage leukaemia (MLL) family of histone H3 lysine 4 (H3K4) methyltransferases. We show here that the DHQY HCF‐1‐binding sequence permits E2F1 to stimulate both DNA damage and apoptosis, and that HCF‐1 and the MLL family of H3K4 methyltransferases have important functions in these processes. Thus, HCF‐1 has a broader role in E2F1 function than appreciated earlier. Indeed, sequence changes in the E2F1 HCF‐1‐binding site can modulate both up and down the ability of E2F1 to induce apoptosis indicating that HCF‐1 association with E2F1 is a regulator of E2F1‐induced apoptosis.     

A COMPASS in the voyage of defining the role of trithorax/MLL-containing complexes: linking leukemogensis to covalent modifications of chromatin

Chromosomal rearrangements and translocations play a major role in the pathogenesis of hematological malignancies. The trithorax-related mixed lineage leukemia (Mll) gene located on chromosome 11 is rearranged in a variety of aggressive human B and T lymphoid tumors as well as acute myeloid leukemia (AML) in both children and adults. It was first demonstrated for the yeast MLL homolog complex, Set1/COMPASS, and now for the MLL complex itself, that these complexes are histone methyltransferases capable of methylating the fourth lysine of histone H3. The post-translational modifications of histones by methylation have emerged as a key regulatory mechanism for both repression and activation of gene expression. Studies from several laboratories during the past few years have brought about a watershed of information defining the molecular machinery and factors involved in the recognition and modification of nucleosomal histones by methylation. In this review, we will discuss the recent findings regarding the molecular mechanism and consequences of histone modification by the MLL related protein containing complex COMPASS.     

Crystal Structure of MLL2 Complex Guides the Identification of a Methylation Site on P53 Catalyzed by KMT2 Family Methyltransferases

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Cell context in the control of self-renewal and proliferation regulated by MLL1

Mixed lineage leukemia 1 (MLL1) is a gene that is disrupted by chromosomal translocation characteristically in a large proportion of infant leukemia and also in a fraction of childhood and adult leukemia. MLL1 encodes a chromatin regulatory protein related to the Drosophila Trithorax protein, a well-studied epigenetic factor that functions during development to maintain expression of its target genes. Although tremendous progress has been made understanding the downstream targets of MLL1 fusion oncoproteins and how manipulation of those targets impacts leukemogenesis, very little is known regarding how the initial expression of an MLL1 fusion protein impacts on that cell’s behavior, particularly how the cell cycle is affected. Here, we focused on the function of endogenous MLL1 in the stem and progenitor cell types that are likely to be transformed upon MLL1 translocation. Our studies reveal a differential response of stem or progenitor populations to acute loss of MLL1 on proliferation and survival. These data suggest that the effects of MLL1 fusion oncoproteins will initiate the leukemogenic process differentially depending on the differentiation state of the cell type in which the translocation occurs.     

Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding

Ash2L is a core component of the MLL family histone methyltransferases and has an important role in regulating the methylation of histone H3 on lysine 4. Here, we report the crystal structure of the N-terminal domain of Ash2L and reveal a new function of Ash2L. The structure shows that Ash2L contains an atypical PHD finger that does not have histone tail-binding activity. Unexpectedly, the structure shows a previously unrecognized winged-helix motif that directly binds to DNA. The DNA-binding-deficient mutants of Ash2L reduced Ash2L localization to the HOX locus. Strikingly, a single mutation in Ash2L(WH) (K131A) breaks the chromatin domain boundary, suggesting that Ash2L also has a role in chromosome demarcation.