The researchers revealed how tumor metabolites block DNA repair

As early as the end of the 19th century, it has been widely studied that genomic instability will lead to the abnormal chromosome number of cancerSubsequently, tumor cells tend to use the discovery of different glucose and energy metabolism pathways from normal cells, which makes the metabolic changes concernedTherefore, genomic instability and metabolic changes are the common characteristics of most tumor cells, but the relationship between these two processes in cancer is rarely reported< br / > recently, nature has revealed how several metabolites accumulated in tumor cells can inhibit DNA repair, thus pointing out the direct relationship between metabolic changes and genomic instability caused by DNA damageThe study was completed by Sulkowski et al< br / > < br / > < br / > mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and idh2) genes cause the accumulation of 2-hydroxyglutarate (2-hg) in cellsMutations in fumarate hydratase (FH) and succinate dehydrogenase (sdhA, SDHB, SDHC and sDHD) genes result in the increase of fumarate and succinate moleculesThe accumulation of these three metabolites will promote the development of tumor, so they are called oncometabolites< br / > α - ketoglutarate (α - kg) is an intermediate product in the Krebs cycle pathway, which is also necessary for α - kg / Fe (II) dependent dioxygenase familyThe family is involved in catalytic oxidation of proteins, DNA, RNA and lipids by binding its α - kg to the active site of enzymeThe metabolites of 2-hg, fumaric acid and succinic acid are similar to α - kg in structure, so they can compete with α - kg to bind to the catalytic site, thus inhibiting these enzymes< br / > among them, lysine histone demethylase (KDM) can modify chromatin, that is, it can catalyze the demethylation of lysine amino acid residue (terminated K9) of DNA binding histone 3 (H3)Closely related are kdm4a and kdm4bThe methylation of H3K9 is linked to the homeostasis dependent repair (HDR) pathway, which can be used to repair double strand breaks (DSBs), the most dangerous type of DNA damage< br / > < br / > < br / > Sulkowski et alFound that tumor metabolites can inhibit the HDR pathway, and confirmed that kdm4a and kdm4b are essential for DSB repairIt was also found that HDR involves the recruitment of multiple repair factor sequences to DSB sites, in which Tip60 protein is the first protein to reach the damaged area, and ATM is also the key protein for DNA repairFor further exploration, they used a system that enables human cells cultured in vitro to precisely start DSB and monitor the repair process< br / > < br / > < br / > by studying HDR in human cancer cells cultured in vitro, it was found that h3k9e3 residue, which was produced by adding 3 methyl groups locally to H3K9 at DSB site, played a key role in the initiation of HDRIn addition, high levels of tumor metabolites inhibited kdm4b in tumor cells with mutations in genes encoding IDH1, idh2, fumarate hydratase or succinate dehydrogenaseThese results indicate that the inhibition of demethylation leads to extensive hypermethylation of H3K9, conceals the specific local appearance of h3k9me3 marker, and damages the recruitment of factors needed for HDR and DSB repair< br / > < br / > < br / > in addition, tumor metabolites not only inhibit the HDR pathway, but also have high sensitivity to the ADP ribose polymerase (PARP) inhibitors in clinical trialsPARP enzyme can promote the repair of single strand DNA breaks, and the inhibitors blocking PARP are used to treat some types of cancerExploring the mechanism of tumor metabolites inhibiting HDR is helpful to provide an effective treatment strategy for tumors caused by the accumulation of metabolites