Novel sub-cellular localizations and intra-molecular interactions may define new functions of Mixed Lineage Leukemia protein

Abstract

Mixed-lineage leukemia (MLL) protein is the best-characterized member of SET family of histone 3 lysine 4 methyltransferase, known for its transcriptional-activation role during development. mll gene rearrangements cause multiple kinds of aggressive leukemia in both children and adults. An important 'first' step in understanding the role of MLL in leukemogenesis would be to identify its localization throughout the cell cycle. In order to fully understand the breath of MLL functions in proliferating cells, we have analyzed its sub-cellular localization during the cell cycle. Our results show that MLL localizes to nucleolus and centrosome in interphase. During mitosis, it localizes to centrosomes and midbody in addition to previously reported spindle apparatus. Our results show that MLL N is required to translocate MLL C to the nucleolus. These finding suggest functional roles for MLL in nucleolus and mitosis. We also show how MLL-fusion proteins (MLL-FPs) localize to the same sub-cellular organelles like endogenous MLL. Our results indicate that MLL-fusion proteins may not only disturb the cell homeostasis by gain-of-function of the chimeric protein, but also by interfering with the functions of endogenous MLL. ARTICLE HISTORY

Moonlighting in Mitosis: Analysis of the Mitotic Functions of Transcription and Splicing Factors

“…Besides being present in the KANSL complex, WDR5 also associates with the MLL N and MLL C subunits of the proteolytically cleaved mixed-lineage leukemia 1 (MLL1/KMT2A) protein, forming a complex with methyltransferase activity that catalyzes trimethylation of histone H3 lysine 4 (H3K4) and positively regulates gene expression [122,123]. The two MLL1 subunits and WDR5 localize to the centrosomes, the spindle, the central spindle, and the midbody dark zone in human cells [124][125][126] (Figure 1). WDR5 also interacts with the MT depolymerase KIF2A, promoting its localization to the spindle poles [125], and with several midbody proteins required for cytokinesis, including PRC1, CEP55, and the centralspindlin components MKLP1/KIF23 and CYK4/RACGAP1 [124].…”

GLP and G9a histone methyltransferases as potential therapeutic targets for lymphoid neoplasms

“…Moreover, studies have also correlated the action of histone methyltransferases (HMTs), particularly Mixed-Lineage Leukemia 1 (MLL1) protein, with the development and progression of ALL. MLL1 protein is known to methylate lysine 4 of H3 histone (H3K4) [ 91 , 98 , 99 ].…”

SET1/MLL family of proteins: functions beyond histone methylation

“… [ 111 , 130 ] Cytokinesis Formation of binucleated cells. [ 111 , 135 ] Cell proliferation Growth arrest at G1 Phase/defects in S-Phase progression. [ 111 ] Ubiquitination process (as E3 ligase) Delayed degradation and increased stability of MLL.…”

“…Enrichment of MLL to the centrosome and spindle compartments suggests important role in spindle assembly [ 130 , 135 ]. Even though only C subunit seems to have a defined role on spindle apparatus, both the subunits of MLL (MLL N and MLL C ) are capable of localizing on the spindles and spindle poles (centrosome) independently throughout mitosis [ 135 ]. Similar to MLL, SETD1A also exhibited staining on spindle apparatus [ 130 ].…”

“…Knockdown of WDR5 hinders the process of abscission (separation of daughter cells) and therefore increases the prevalence of multi-nucleated cells, which is a hallmark for cytokinesis failure [ 138 ]. Similarly, MLL can be detected at the midbody in mammalian cells, and depletion of MLL leads to binucleated cells, most likely due to failed cytokinesis [ 111 , 135 ]. However, how exactly MLL is targeted to the midbody and controls the cytokinesis process is yet to be elucidated.…”