Topological Features of Histone H2A Monoubiquitination
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HEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY
Topological Features of Histone H2A Monoubiquitination A. A. Kudriaevaa,*, Corresponding Member of the RAS V. M. Lipkina, and A. A. Belogurov, Jr.a,b Received March 23, 2020; revised April 15, 2020; accepted April 15, 2020
Abstract—The cellular response to DNA damage protects the essential information stored in the genome. This mechanism is crucial in terms of the cancer prevention and aging progression. The DNA damage response (DDR) consists of a complex network controlling the cell cycle and multiple mechanisms of the DNA repair. The DDR disruption is a cornerstone feature of the tumor cells, which allows them to enhance beneficial mutations that prevent successful disease treatment. The important checkpoints of the DDR are currently poorly understood due to the complexity and diversity of the DNA repair machinery. Histone ubiquitination is intensively involved in the repair of the double-stranded DNA breaks. This post-translational modification is known to be a key factor in the recruitment of the repair factors to the DNA damage sites. Here, the crucial role of the ubiquitin lysine residue K27 in the process of histone H2A monoubiquitination mediated by the ubiquitin ligase RNF168 has been showed. The presented data suggest forced and intensive diffusion of ubiquitin from the cytoplasm to the nucleus, which is characterized by the dynamic equilibrium less than 10 min. The comparison of the turnover rate of the wild-type ubiquitin and its variant with a single functional lysine residue K27 suggests an important role of the ubiquitin deposition as a covalent conjugate with histone H2A in terms of the stability of the entire ubiquitinome. Keywords: histones, ubiquitin ligases, ubiquitination, chromatin, DNA repair, double-stranded DNA breaks DOI: 10.1134/S1607672920040079
Maintaining genome stability is essential for cell homeostasis and strongly depends on the accuracy of DNA replication, chromosome segregation, and DNA repair. DNA damage may occur under the influence of various factors such as chemical carcinogens in the environment, metabolites produced by intestinal microbiota, free radicals produced by activated immune cells (monocytes and macrophages), ultraviolet and ionizing radiation, as well as some pharmaceuticals (e.g., genotoxic antitumor drugs) [1]. These and other factors cause gene mutations and damage to chromosomes. Depending on the type of DNA damage and the cell-cycle stage, various cellular responses are used for repair [2]. They have a common principle of action: DNA damage causes changes in its structure or replication stop, which is recognized by sensory proteins. These proteins recruit signaling and downstream effector proteins, which, in turn, initiate cascades that trigger cellular processes to repair DNA damage or eliminate cells with irreparable changes. The repair of DNA damage (especially doublestranded breaks, which are considered the most dangerous) is crucial for maintaining the genome integrity and cell homeostasis [3]. The cellular re
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