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Review
. 2015 Jun;15(6):334-46.
doi: 10.1038/nrc3929.

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Rajesh C Rao  1 , Yali Dou  2
Affiliations
Review

Hijacked in cancer: the KMT2 (MLL) family of methyltransferases

Rajesh C Rao et al. Nat Rev Cancer. 2015 Jun.

Abstract

Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility. Although the human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member KMT2A in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.

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Figures

Figure 1
Figure 1. Metazoan KMT2 family histone methyltransferases
a. Schematic representation of domain structures for each KMT2. KMT2A and KMT2B have the consensus D/GVDD sites (indicated by arrow) that are cleaved by Taspase 1, at two conserved sites for KMT2A and at one conserved site for KMT2B. This cleavage unique feature for this KMT2 subgroup. The resulting large N-terminal fragment and a smaller C-terminal fragment subsequently associate through FYRN and FYRC domains to generate a functional, noncovalent heterodimeric complex. KMT2C and KMT2D contain two clusters of PHD domains as well as the juxtaposed FYRN, FYRC and the SET domains on the C-terminus. One HMG-I binding motif and multiple nuclear receptor interacting motifs (LXXLL) are present in the protein sequences. These motifs are frequently found in transcription factors and cofactors. The PHD4–6 domains of KMT2C and KMT2D are able to bind unmethylated and asymmetrically di-methylated H4 arginine 3 (H4R3me0 and H4R3me2a), supporting a coordinated function with protein arginine methyltransferases. KMT2F and KMT2G are the smallest KMT2 subgroup and contain an N-terminal RNA recognition motif (RRM) and a C-terminal N-SET domain, which interact with WDR82 and ubiquitylated histone H2B respectively. b. Schematic representation of interactions among KMT2A core subunits as well as their interactions with chromatin. KMT2A core complex is stabilized by pair-wise interactions between KMT2A (WIN)-WDR5, WDR5-RbBP5 (VDV), RbBP5-ASH2L and ASH2L-DPY30. KMT2A, pink; WDR5, blue; RbBP5, green; ASH2L, purple; DPY30, red. Furthermore, KMT2A is stabilized on chromatin through multivalent interactions, which include interactions of the AT hook and CxxC domain with AT-rich sequence and non-methylated CpG dinucleotides , respectively; as we as interactions between PHD and Bromo-domains with H3K4me3 and acetylated lysine residues, respectively. The coupling of the enzyme with binding domains for its methylation product(s) is important for feed-forward maintenance of H3K4me in cells. Transient interactions between SET and histone H3 tail as well as ASH2L PHD and ubiquitin are also reported.
Figure 2
Figure 2. Distinct distributions of KMT2 enzymes at transcription regulatory regions
Based on KMT2 functional domains, their respective interaction with chromatin and substrate specificity, it is envisioned that KMT2C and KMT2D are the predominant KMT2s at distal enhancers while KMT2F and KMT2G are the major enzymes at gene promoters. KMT2A and KMT2B could function at both regulatory regions. The distribution of KMT2 enzymes in the genome is consistent with distribution of histone H3 K4 methylation, i.e. H3K4me1 is a predominant histone mark at cell-type specific distal regulatory enhancers and H3K4me3 is mainly found at actively transcribed gene promoters. Recruitment of KMT2 to different genomic regions is also facilitated by their interactions with sequence specific transcription factors or RNA polymerase II (RNAPII), which leads to non-coding and coding transcription at enhancers and promoters, respectively.
Figure 3
Figure 3. Schematic for the pathogenesis of MLL
As detailed in Box 2, both wild type KMT2A and MLL fusion proteins contribute to the regulation of leukemia signature genes. While KMT2A functions in transcription initiation through its H3K4 methyltransferase activity, MLL fusion proteins function to recruit transcription cofactors such as MENIN, DOT1L, P-TEFb, LEDGF, and CBX8–TIP60 to promote transcription elongation. Small molecules targeting each of these steps have shown efficacies in MLL cell lines and represent potential therapeutic strategy. References see text.
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