Polycomb Alterations in Acute Myeloid Leukaemia: From Structure to Function

Epigenetic dysregulation is a hallmark of many haematological malignancies and is very frequent in acute myeloid leukaemia (AML). A cardinal example is the altered activity of the Polycomb Repressive Complex 2 (PRC2) due to somatic mutations and deletions in genes encoding PRC2 core factors that are necessary for correct complex assembly. These genetic alterations typically lead to reduced histone methyltransferase activity that, in turn, has been strongly linked to poor prognosis and chemoresistance. In this review, we provide an overview of genetic alterations of PRC components in AML, with particular reference to structural and functional features of PRC2 factors. We further review genetic interactions between these alterations and other AML-associated mutations in both adult and paediatric leukaemias. Finally, we discuss reported prognostic links between PRC2 mutations and deletions and disease outcomes and potential implications for therapy

Genome-Wide Search for Tyrosine Phosphatases in the Human Genome Through Computational Approaches Leads to the Discovery of Few New Domain Architectures

Reversible phosphorylation maintained by protein kinases and phosphatases is an integral part of intracellular signalling, and phosphorylation on tyrosine is extensively utilised in higher eukaryotes. Tyrosine phosphatases are enzymes that not only scavenge phosphotyrosine but are also involved in wide range of signalling pathways. As a result, mutations in these enzymes have been implicated in the pathogenesis of several diseases like cancer, autoimmune disorders, and muscle-related diseases. The genes that harbour phosphatase domain also display diversity in co-existing domains suggesting the recruitment of the catalytic machinery in diverse pathways. We have examined the current draft of the human genome, using a combination of 3 sequence search methods and validations, and identified 101 genes encoding tyrosine phosphatase-containing gene products, agreeing with previous reports. Such gene products adopt 37 unique domain architectures (DAs), including few new ones and harbouring few co-existing domains that have not been reported before. This semi-automated computational approach for detection of gene products belonging to a particular superfamily can now be easily applied at whole genome level on other mammalian genomes and for other protein domains as well

Structural rationale to understand the effect of disease-associated mutations on Myotubularin

Myotubularin or MTM1 is a lipid phosphatase that regulates vesicular trafficking in the cell. The MTM1 gene is mutated in a severe form of muscular disease, X-linked myotubular myopathy or XLMTM, affecting 1 in 50,000 newborn males worldwide. There have been several studies on the disease pathology of XLMTM, but the structural effects of missense mutations of MTM1 are underexplored due to the unavailability of a crystal structure. MTM1 consists of three domains-a lipid-binding N-terminal GRAM domain, the phosphatase domain and a coiled-coil domain which aids dimerisation of Myotubularin homologs. While most mutations reported to date map to the phosphatase domain of MTM1, the other two domains on the sequence are also frequently mutated in XLMTM. To understand the overall structural and functional effects of missense mutations on MTM1, we curated several missense mutations and performed in silico and in vitro studies. Apart from significantly impaired binding to substrate, abrogation of phosphatase activity was observed for a few mutants. Possible long-range effects of mutations from non-catalytic domains on phosphatase activity were observed as well. Coiled-coil domain mutants have been characterised here for the first time in XLMTM literature