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DNA methylation is an epigenetic modification essential for regulation of cell processes such as chromatin condensation, transcription, gene imprinting and cell differentiation. In mammals, DNA methylation at CpG sites is established by cytosine-C5 DNA methyltransferases (MTases) which form specific DNA methylation patterns. During malignant diseases progression, different multiple changes both in DNA methylation patterns and in MTase genes were observed. Human de novo MTase DNMT3A is most frequently mutated in acute myeloid leukemia (AML) with striking prevalence of R882H mutation. R882H has been extensively studied and its potential carcinogenic effect has been suggested. Here, we investigate the role of the other missense mutations in DNMT3A catalytic domain found in AML (S714C, R635W, R736H, R771L, P777R, and F752V) using accordingly mutated murine Dnmt3a catalytic domain and short CpG-containing DNA substrates as model system. The 3-5-fold decrease of initial methylation rates was observed for R181L (R771L), S124C (S714C) and P187R (P777R) with conserved ability to bind DNA. In the case of F152V (F752V), R45W(R635W) and R146H (R736H) a complete loss of the methylation activity was observed accompanied with the loss of DNA binding for R45W and R146H. Strikingly, all the mutations except S124C (S714C) are not located in the DNMT3A catalytic loop. The importance of these amino acids for the proper DNMT3A inner contacts formation was suggested. The ability of the DNMT3A partner protein DNMT3L to restore the methylation activities of S124C (S714C) and R181L (R771L) was revealed. The role of aberrant DNMT3a activity in AML was discussed on the basis of our knowledge of how these mutations affect methylation function and via the computer modelling. This work was supported by the RFBR grant 19-04-00533.
№ | Имя | Описание | Имя файла | Размер | Добавлен |
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1. | Poster_Khrabrova.pdf | Poster_Khrabrova.pdf | 97,7 КБ | 25 декабря 2019 [KirsanovaOV] |