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    • The above inferences concluded that histidine is enhancing t

    2022-05-27

    The above inferences concluded that histidine is enhancing the overall stability and rigidity of the protein which further might be restraining the protein during the transition from inactive to active state and vice-versa present in the SANT domain. Since the SANT domain binds with histone via electrostatic interaction so the variant protein containing histidine (basic amino acid) at the 193rd position will generate +/+ repulsion between SANT domain and histone protein. This domain might be responsible for pre-initiation interaction with substrate thereby facilitating the binding of lysine peptide in the groove of the active site for the catalytic function of the EZH2 protein. The above findings are upheld by I-Mutant v2.0, that speculated increased stability of the protein by D> H change. The epidemiological data on rs2302427 D > H of human EZH2 gene has shown that mutant allele (C> G) is acting as an protective change among various populations (white Caucasians, Koreans, Taiwan, Chinese) in diseases such as hepatocellular cell carcinoma, oral cancer, gastric cancer, prostate cancer, urothelial cell carcinoma, cholangiocarcinoma and breast cancer (Bachmann et al., 2005, Yoon et al., 2010, Yu et al., 2013, Paolicchi et al., 2013, Zhou et al., 2014, Yu et al., 2014, Tao et al., 2015, Gao et al., 2015, Jung Su et al., 2015, Lee et al., 2018, Ling et al., 2018). The variant amino Poly (A) Tailing expressing more in healthy individuals might be reducing the methyl transferase activity of EZH2 gene thereby reducing its oncogenic effect.
    Conclusion The present study has demonstrated, 12 SNPs in the EZH2 gene are functionally important to its structure and function. Out of these 12 SNPs only 6 SNPs are studied as discussed above but no data is available, till date, for the remaining 6 SNPs (rs1996996, rs73158274, rs10952783, rs2177567, rs1880357 and rs73158280), hence need to be studied. As we discussed that rs17171119 has only one study so this SNP ID need more exploration. The SNP ID rs3217095 demands extensive research to elucidate that how exactly it is influencing the miRNA interaction withEZH2 gene. So in future, we can have a deep understanding of transcriptional regulation of EZH2 gene. The present study has given a novel insight for aspartic acid to histidine change (rs2302427 D> H, C> G) at the 193rd position and its impact on the structural and catalytic function of the SET domain via influencing the interaction of SANT domain with histone protein. Such in-silico based SNP analysis may broaden our understanding of the genotype-phenotype relationship. The present findings may help us in understanding the molecular pathway of EZH2 in tumorigenesis with extensive detail so that effective drug discoveries can be done in near future in order to halt the overexpression of EZH2 gene so the aggressiveness of disease can be precluded, especially in case of cancers. By knowing the effect of cSNPs change of EZH2 gene at the proteomic level, there can be a scope for the development of more specific and less toxic EZH2 inhibitors. This study also provides a guideline to the fellow researchers to understand and then to explore the importance of these SNPs in the etiology of complex diseases.
    Acknowledgments
    Introduction Enzymatic inhibition of EZH2, the enzymatic subunit of the polycomb repressive complex 2 (PRC2) that plays a pivotal role in catalyzing the methylation of the lysine 27 of histone H3 (H3K27), has been intensively explored as cancer therapy. Two leading compounds, EPZ-6438 and GSK126, demonstrate preliminary benefits in a small subset of hematological malignances, including diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (Kurmasheva et al., 2017, Lee et al., 2014, McCabe et al., 2012b) bearing EZH2 gene mutations. EZH2 mutations result in constitutively activated EZH2 enzymatic activity and are believed to drive a H3K27 methylation (H3K27me)-dependent cell growth resembling well-defined oncogenic drivers (Brach et al., 2017, Huet et al., 2017, McCabe et al., 2012a, Morin et al., 2010). However, EZH2 mutations occur in a very small subset of hematological tumors. In most solid tumors, EZH2 is present in an overexpressed wild-type form that similarly bears H3K27me catalyzing activity. It remains unclear, however, whether overexpressed wild-type EZH2 could also functionally result in growth dependency of H3K27me. Insights in trilobites regard may expand the therapeutic benefits of EZH2 inhibitors (EZH2is) to a broad spectrum of solid tumors (Bachmann et al., 2006, Bracken et al., 2003, Kim and Roberts, 2016, McCabe et al., 2012b, Sun et al., 2016, Varambally et al., 2002).