Inhibitors of Protein Methyltransferases as Chemical Tools

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DNA double-strand breaks Introduction DNA double-strand breaks DSBs) are the most dangerous lesions induced by a variety of treatments including ionizing radiation IR)

A sequence variant of histone H2A called H2AX is one of

A sequence variant of histone H2A called H2AX is one of the important components of chromatin involved in DNA damage response induced by different genotoxic tensions. loss in normal cells and tissues as well as in those deficient in ATM, DNA-PK, and DSB repair proteins activity. The results of the latest scientific research of the low-dose irradiation phenomenon are offered including the bystander effect and the adaptive Piboserod IC50 response estimated by H2AX detection in cells and tissues. Keywords: Phosphorylation, Histone H2AX, Dephoshorylation, DNA double-strand breaks Introduction DNA double-strand breaks (DSBs) are the most dangerous lesions induced by a variety of treatments including ionizing radiation (IR), radiomimetic drugs, and lasers action. DSB removal is usually determinated by DSB repair system efficiency and is usually crucial for cell survival. Unsuccessful DSB repair prospects to the appearance of chromosomal aberrations in mitosis and potentially could induce malignancy. Considerable studies have discovered the mechanisms of DSB repair that include non-homologous end-joining (NHEJ) and homologous recombination (HR). DSB repair pathways compete with each other, and the choice between them is usually dependent on the manifestation of specific protein factors and the cell cycle phase. The studies of sensitivity to IR of different mutant vertebrate cell lines have led to a conclusion that NHEJ pathway plays a dominating role in DSB repair during G1-early S phase, Piboserod IC50 but could run during the whole cell cycle, while HR is usually preferentially used in late S-G2 phase (Takata et al. 1998; Shrivastav et al. 2008). It has been shown, using fluorescent reporter assay for the study of DSB repair induced by endonuclease, that the input of NHEJ in human cells is usually higher than HR during the whole cell cycle. NHEJ activity increases from G1 to G2/M stage, and HR is usually absent in G1, most active in S, and decreases while cells progress to G2/M stage (Mao et al. 2008). H2AX is usually a variant of histone H2A in mammalian cells. The appearance of phosphorylated form of this histone, called H2AX, is usually one of the earliest events involved in DNA damage response (DDR) to different genotoxic tensions that induce DSBs. The users of phosphotidylinositol 3-kinase family (PI3) ATM and DNA-PK are activated in response to DNA DSB induction by IR and phosphorylate protein involved in cell cycle arrest and DNA repair (Rogakou et al. 1998; Yang et al. 2003; Kurz and Lees-Miller 2004). H2AX is usually phosphorylated by these kinases on serine 139 within moments Piboserod IC50 after IR. The phosphorylated form of this histone DHX16 spreads in both directions from DSB and occupies megabase chromatin domain names (Rogakou et al. 1998; Rogakou et al. 1999; Redon et al. 2002; Sedelnikova et al. 2003). DSBs induced during S phase after the action of brokers inhibiting replication like UV, hydroxyurea, or topoisomerase Piboserod IC50 poisons require activation of ATR kinase for H2AX phosphorylation at the sites of stalled replication forks (Ward and Chen 2001; Ward et al. 2004). Chemical and environmental brokers that do not induce DSBs also could lead to H2AX phosphorylation. For example, the treatment of cells with chemical potent carcinogen benz[a]pyrene prospects to formation of covalent DNA adducts that induce H2AX phosphorylation in ATM-, ATR-, and DNA-PK-dependent manner (Yan et al. 2011). H2AX phosphorylation could be induced in DNA in the absence of DSBs by hyperthermia (Search et al. 2007). Heat-induced H2AX foci are ATM- or Piboserod IC50 DNA-PK-dependent and are observed in all phases of cell cycle, but the precise mechanisms involved in foci formation are.




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