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Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
In a similar line of investigation, Sulkowski et al. (2020) ascertained a connection between 2-HG, succinate, fumarate and DNA repair. The TCA cycle metabolites inhibit the lysine demethylase KDM4B, resulting in aberrant hypermethylation of H3K9 at loci in close proximity to DNA double-strand breaks. This conceals a local H3K9 trimethylation signal that is essential for the proper functioning of the DNA homology-dependent repair (HDR) pathway. Consequently, the recruitment of salient HDR transcriptional regulators – Tip60 and ATM – is impaired at DNA break sites leading to reduced end resection. Of note is the increased TCA cycle activity of succinate and fumarate commonly observed in exercise (Brugnara et al., 2012), and it is thus plausible that a disruption in chromatin signalling and DNA repair, as outlined, may be exacerbated in certain forms of exercise that activate the oxidative phosphorylation pathway.
Tumor hypoxia: an important regulator of tumor progression or a potential modulator of tumor immunogenicity?
Published in OncoImmunology, 2021
Goutham Hassan Venkatesh, Raefa Abou Khouzam, Walid Shaaban Moustafa Elsayed, Nagwa Ahmed Zeinelabdin, Stéphane Terry, Salem Chouaib
DNA repair processes are intricately dependent on several metabolic pathways for maintenance of genome stability. DNA damage signaling kinases regulate the metabolic state of the cell through production of nucleotides required for repair, lactate mediated chromatin remodeling to enhance DNA repair gene transcription.32 Chronic hypoxia promotes the buildup of various enzymes related to glycolysis and tricarboxylic acid cycle oncometabolites such as 2-hydroxyglutarate, fumarate, and succinate, that could impede DNA repair.4 For example, 2-hydroxyglutarate inhibits the lysine demethylase KDM4B which acts on histone H3 proteins and contribute to impediment of homology-directed rejoining.4 Furthermore, re-oxygenation after acute hypoxia can result in an increase in reactive oxygen species (ROS) and a decrease in mitochondrial ATP generation, which in turn may induce alterations in DNA damage checkpoints and contribute to genomic instability.4
Small molecule KDM4s inhibitors as anti-cancer agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Hongzhi Lin, Qihang Li, Qi Li, Jie Zhu, Kai Gu, Xueyang Jiang, Qianqian Hu, Feng Feng, Wei Qu, Yao Chen, Haopeng Sun
KDM4A (JmjD2A/JHDM3A) and other members (KDM4B/JmjD2B/JHDM3B, KDM4C/JmjD2C/JHDM3C, and KDM4D/JmjD2D/JHDM3D) in KDM4 subfamily are earliest identified as JmjC KDMs which can catalyze the demethylation of histone H3 subunit lysine9 tri-/di-methylated mark (H3K9me3/2)18. High expressions of KDM4s are considered as promote oncogenesis in some types of cancers, including prostate19, breast20,21, colon22, and some others15. Downregulation of KDM4s via molecular biology methods or inhibition of their catalytic activity by small molecule inhibitors is confirmed as strategy for oncotherapy16. In recent decades, increasing attention is focused on the development of KDM4s inhibitors as antitumor agents. Meanwhile, a number of inhibitors have been disclosed by medicinal chemists. Recently, some potent and selective JmjC KDM inhibitors were reported. Although the good clinical candidates are still undiscovered, many publications have reported various modulators with different chemotypes under the guide of different design strategies or screen assays (especially high-throughput screen, HST). Although some excellent reviews have summarized the development of KDM4s inhibitors23–29, it is necessary to provide an update for new drug discovery and design works.
The relationship between histone posttranslational modification and DNA damage signaling and repair
Published in International Journal of Radiation Biology, 2019
Ajit K Sharma, Michael J. Hendzel
H3K9me3 also serve as a docking site for a repressive complex containing the histone methyltransferase SUV39H1, KAP1 and HP1 at DSBs (Ayrapetov et al. 2014). Recruitment of SUV39H1 to damaged DNA mediates the local spreading of H3K9me3 surrounding DSBs, which further activates TIP60 and TIP60-mediated activation of ATM by acetylation. Activated ATM then phosphorylates KAP1 to release the repressive complex i.e. SUV39H1-KAP1-HP1 complex from damaged chromatin (Ayrapetov et al. 2014). Overall these results reveal that H3K9me3 regulates the DDR by recruiting Tip60 at DSBs site in order to activate ATM and thus H3K9me3 play key role in early sensing of the damage DNAs. Histone H3K9 methylation is also important in the establishment of heterochromatin, where it is required for the recruitment of HP1 proteins. As discussed earlier, this heterochromatin barrier is disassembled for efficient repair of heterochromatin-associated breaks in an ATM-dependent manner. Further macroH2A1 and PRDM2 accumulated at double-strand break, along with an enrichment of the PRDM2 mediated H3K9me2 (Khurana et al. 2014). Loss of either macroH2A1 or PRDM2 impairs the retention of BRCA1, but not 53BP1, at DSBs and reduces DNA end resection in human cells (Khurana et al. 2014). In addition to the involvement of H3K9me3 methyltransferases in the DDR, histone demethylases like KDM4B and KDM4D are also known to be recruited to damaged sites in human cells (Young et al. 2013; Khoury-Haddad et al. 2014). We found that KDM4B recruitment was dependent on poly (ADP-ribose) polymerase 1 activity and led to a transient reduction of H3K9me2 and H3K9me3 following 2 Gy of γ-irradiation (Young et al. 2013). KDM4D was also found to be directly PARylated by PARP1 in response to DNA damage induced by etoposide and camptothecin (Khoury-Haddad et al. 2014).