Molecular dynamics approach to identification of new OGG1 cancer-associated somatic variants with impaired activity
| Autor: | Kristina A. Makasheva, Darya D. Yatsenko, Anna V. Yudkina, Darya Yu. Raspopova, Alexander E. Barmatov, Dmitry O. Zharkov, Anton V. Endutkin, Aleksandr V. Popov, Evgeniia A. Diatlova |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
structure–function Protein Conformation alpha-Helical Lung Neoplasms DNA Repair Mutant Gene Expression Biochemistry AP apurinic/apyrimidinic DNA Glycosylases chemistry.chemical_compound genetic polymorphism THF (3-hydroxytetrahydrofuran-2-yl)methyl phosphate OGG1 BER base excision repair Principal Component Analysis Leukemia Base excision repair personalized medicine DNA Neoplasm MD molecular dynamics Neoplasm Proteins oxoG 8-oxoguanine protein function prediction Research Article OGG1 8-oxoguanine DNA glycosylase Protein Binding Guanine DNA repair DNA damage COSMIC Catalogue Of Somatic Mutations In Cancer Computational biology Biology Molecular Dynamics Simulation 03 medical and health sciences Humans Protein Interaction Domains and Motifs Molecular Biology PCA Principal component analysis Binding Sites 030102 biochemistry & molecular biology oxodG 8-oxo-2′-deoxyguanosine Cell Biology Small Cell Lung Carcinoma 8-Oxoguanine molecular dynamics Protein Structure Tertiary Kinetics 030104 developmental biology chemistry Amino Acid Substitution DNA glycosylase Cancer cell Mutation Protein Conformation beta-Strand DNA |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | DNA of living cells is always exposed to damaging factors. To counteract the consequences of DNA lesions, cells have evolved several DNA repair systems, among which base excision repair is one of the most important systems. Many currently used antitumor drugs act by damaging DNA, and DNA repair often interferes with chemotherapy and radiotherapy in cancer cells. Tumors are usually extremely genetically heterogeneous, often bearing mutations in DNA repair genes. Thus, knowledge of the functionality of cancer-related variants of proteins involved in DNA damage response and repair is of great interest for personalization of cancer therapy. Although computational methods to predict the variant functionality have attracted much attention, at present, they are mostly based on sequence conservation and make little use of modern capabilities in computational analysis of 3D protein structures. We have used molecular dynamics (MD) to model the structures of 20 clinically observed variants of a DNA repair enzyme, 8-oxoguanine DNA glycosylase. In parallel, we have experimentally characterized the activity, thermostability, and DNA binding in a subset of these mutant proteins. Among the analyzed variants of 8-oxoguanine DNA glycosylase, three (I145M, G202C, and V267M) were significantly functionally impaired and were successfully predicted by MD. Alone or in combination with sequence-based methods, MD may be an important functional prediction tool for cancer-related protein variants of unknown significance. |
| Databáze: | OpenAIRE |
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