User:Sumit Kamat/Sandbox Reserved 901

Overview

Histone-lysine N-methyltransferase 2A (KMT2A) known as acute lymphoblastic leukemia 1 (ALL-1) is an enzyme that in humans is encoded by the KMT2A gene. KMT2A gene is a histone methyltransferase which are histone modifying enzymes which catalyze the transfer of methyl groups to lysine and arginine residues of histone proteins. The KMT2A gene is a positive global regulator of gene transcription and comprises of transactivation domain 9aaTAD which is involved in the epigenetic maintenance of transcriptional memory ^[1]. The KMT2 family can mono-, di- and trimethylates histone H3K4. This family of enzymes is found within a macromolecular complex known as the COMPASS family and are highly conserved from yeast to human ^[2].

.Figure Showing the Binary Complex of the Mixed Lineage Leukaemia (MLL1) SET Domain with the cofactor product S-Adenosylhomocysteine.

Function

The KMT2A gene encodes a protein which is contains multiple conserved domains. KMT2A gene encodes a transcriptional coactivator that plays an important role in regulating gene expression during early development and hematopoiesis. Out of the many domains, SET domain is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation ^[3].The SET1 and MLL (KMT2) methyltransferases are conserved from yeast through humans. The Saccharomyces cerevisiae genome encodes a single H3K4 methyltransferase, Set1, whereas humans possess at least six homologs: SET1a, SET1b and MLL1-4. Unlike many SET domain enzymes, SET1 and MLL KMTs display very weak activity toward H3K4 and require additional subunits to attain maximal activity ^[4]. MLL1 was found to be involved in chromosomal translocations in a variety of acute lymphoid and myeloid leukaemias ^[5].

Figure 1. Binding Domain pocket of KMT2A SET Domain with the cofactor product S-Adenosylhomocysteine.

Disease

Relevance

Structural highlights

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References

1. ↑ Ziemin-van der Poel S, McCabe NR, Gill HJ, Espinosa R 3rd, Patel Y, Harden A, Rubinelli P, Smith SD, LeBeau MM, Rowley JD, et al.. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10735-9. doi:, 10.1073/pnas.88.23.10735. PMID:1720549 doi:http://dx.doi.org/10.1073/pnas.88.23.10735
2. ↑ PMC3711870
3. ↑ PMC 3225774
4. ↑ PMC3711867
5. ↑ Eissenberg JC, Shilatifard A. Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Dev Biol. 2010 Mar 15;339(2):240-9. doi: 10.1016/j.ydbio.2009.08.017. Epub 2009 Aug 21. PMID: 19703438; PMCID: PMC3711867