MLL5 (KMT2E): structure, function, and clinical relevance

Abstract

The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A-2D and 2F-2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates. MLL5 has been reported to play key roles in diverse biological processes, including cell cycle progression, genomic stability maintenance, adult hematopoiesis, and spermatogenesis. Recent studies of MLL5 variants and isoforms and putative MLL5 homologs in other species have enriched our understanding of the role of MLL5 in gene expression regulation, although the mechanism of action and physiological function of MLL5 remains poorly understood. In this review, we summarize recent research characterizing the structural features and biological roles of MLL5, and we highlight the potential implications of MLL5 dysfunction in human disease.

Keywords: Cancer; Cell division; Hematopoietic stem cell differentiation; Histone methylation; Leukemia; PHD finger.

Fig. 1

Schematic representation of human MLL5 protein and its three isoforms with their mRNA organizations. Each protein has a conserved PHD finger and a single SET domain. Full-length HsMLL5 gene consists of 25 coding exons, which produces a protein of 1858 amino acids. HsMLL5α is translated from coding exon 1 to exon 13 with an extra sequence located in the intron following coding exon 13 (labeled as I13) of full-length HsMLL5. This extra sequence translates into the last 35 amino acids of HsMLL5α (yellow square). HsMLL5β has the same sequence as full-length HsMLL5 from coding exon 1 to part of exon 12, where it is truncated by a 26-bp sequence. HsMLL5β protein has a single amino-acid difference compared with full-length HsMLL5 (red line). NKp44L mRNA lacks coding exon 21 to exon 25, and contains an extra sequence located in the intron following coding exon 20 (labeled as I20). I20 translates into the last 12 amino acids, which are specific to NKp44L (purple square)

Fig. 2

Post-translational modifications and binding partners responsible for the biological functions of MLL5 protein. The 1858 amino-acid HsMLL5 protein can be divided into three regions: the PHD/SET domain (PS, 1-561 aa), central domain (CD, 562–1122 aa), and C-terminal domain (CT, 1113–1858 aa). Two phosphorylation sites (yellow ellipses) are indicated together with the protein kinases known to phosphorylate HsMLL5. The Plk1 protein-binding motif (PBD, T887/S888/T889) is indicated by the green square. The CD domain is involved in interactions with p53 tetramer, Plk1, and Borealin. Putative partners, based on studies with MLL5 isoforms and orthologs, are also shown in blue- and red-dotted ellipses, respectively

Fig. 3

MLL5 gene alterations according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database in human tumors. All informations are acquired using the keyword “MLL5” on 3 September 2016. All synonymous mutations are excluded. a MLL5 gene somatic mutation rate; b MLL5 gene overexpression and repression rate