Key Points
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The histone–lysine N-methyltransferase (KMT2) family comprises a set of lysine methyltransferases that methylate the lysine 4 residue on histone H3 (H3K4). KMT2 family members demonstrate different substrate specificity in vitro and their methyltransferase activities are dependent, to varying degrees, on association with three core subunits (WD repeat protein 5, retinoblastoma binding protein 5 and ASH2L).
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KMT2 family members have intrinsically different biochemical properties and are recruited to different genomic regions owing to their distinct domain structures and distinct interacting proteins.
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KMT2 family members have important roles in transcription regulation. Among them, KMT2C and KMT2D are crucial for monomethylation of H3K4 at distal regulatory enhancers, whereas KMT2F and KMT2G are responsible for the majority of H3K4 trimethylation at transcription start sites.
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There is extensive interplay between KMT2-dependent H3K4 methylation and DNA methylation, underlying the potential epigenetic stability of this histone methylation.
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Mutations in the KMT2 family are among the most common genetic aberrations in human cancer — including haematological malignancies as well as solid tumours, such as large intestine, lung, endometrial, breast, bladder and brain cancers.
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Mutations in the KMT2 family frequently involve the SET domain and the plant homeotic domains. Of somatic mutations in cancers with known zygosity, heterozygous mutations predominate. These features suggest that the wild-type KMT2 allele may be required for tumour survival, similar to KMT2A-rearranged mixed lineage leukaemia.
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KMT2 family members may have distinct roles in cancer. Although it remains unclear whether cancer-derived KMT2 mutations are 'drivers' or 'passengers', mechanistic studies in animal models suggest that KMT2C may be a tumour suppressor and KMT2A and KMT2D may be proteins derived from proto-oncogenes.
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The targeting of the fusion protein and wild-type KMT2A, as well as their interacting proteins, has emerged as a promising strategy to treat mixed lineage leukaemia, and may apply more broadly to a variety of cancers.
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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Acknowledgements
The authors thank G. Dresslor and K. Ge for critical reading of the manuscript. The authors recognize that they were unable to cover some important aspects of KMT2 biology, especially discoveries carried out in model organisms and KMT2A aberration in MLL, in this Review. The authors apologize to those that they have not been able to reference owing to space constraints. The funding is provided by the US National Institutes of Health (GM082856 to Y.D. and EY022299 to R.C.R.), the Leukemia and Lymphoma Society (LLS), American Cancer Society (ACS) and Stand Up to Cancer to Y.D.; Research to Prevent Blindness, and Knights Templar Eye Foundation to R.C.R.
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Glossary
- AT-rich sequence
-
A DNA sequence with a higher frequency of adenosine and thymidine that can be found in specific genomic regions such as transcription start sites (TATA boxes) or replication initiation sites in bacteria. It can be specifically bound by several protein motifs such as AT-hook, HMG motif and B-box zinc finger.
- CpG dinucleotides
-
A cytosine and a guanine nucleotide separated by one phosphate. The frequency of CpG dinucleotides in human genomes is extremely low (∼1%), and most are methylated to form 5-methylcytosine. A relatively high level of unmethylated CpG dinucleotides is usually associated with promoters of actively transcribed genes.
- H3K79me
-
Histone H3 lysine 79 methylation is deposited by histone methyltransferase DOT1L. H3K79me is commonly found in the transcribed gene-coding regions and is considered a histone mark for transcription elongation.
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Rao, R., Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer 15, 334–346 (2015). https://doi.org/10.1038/nrc3929
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DOI: https://doi.org/10.1038/nrc3929
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