How tumor metabolites block DNA repair

As early as the end of the 19th century, abnormalities in the number of cancer chromosomes caused by genomic instability were widely studied, and subsequent findings that tumor cells tended to use different pathways of glucose and energy metabolism than normal cells led to changes in metabolism. As a result, genomic instability and metabolic changes are common features of most tumor cells, but little has been reported about the link between the two processes in cancer.Recently, the journal Nature revealed how several metabolites that accumulate at higher levels in tumor cells inhibit the mechanisms of DNA repair, suggesting a direct link between metabolic changes and genomic instability caused by DNA damage. The study was conducted by Sulkowski et al., of Yale University School of Medicine.Isocitrate dehydrogenase 1 and 2 (isocitrate dehydrogenase 1 and 2, IDH1 and IDH 2) gene mutations cause a large accumulation of metabolites 2-hydroxyglutarate (2-hydroxyglutarate, 2-HG) in cells. Genetic mutations in the fumarate hydrase (FH) and succinate dehydrogenase (SDHA, SDHB, SDHC and SDHD) led to an increase in the molecules of Yanhuso acid and sdhour. The accumulation of all three metabolites promotes tumor development and is therefore known as tumor metabolites.α-ketoglutarate (α-ketoglutarate, α-KG) is an intermediate product of the Krebs cycle path and a substance necessary for the α-KG/Fe(II) dependent on the bioxygenase family. The family binds α enzyme-active sites through its enzyme-KG, which in turn participates in oxidation reactions in catalytic proteins, DNA, RNA and lipids. The three metabolites, 2-HG, Yanhuso acid and amber acid, are structurally similar to α-KG, so they can bind to the catalytic site in competition with α-KG to inhibit these enzymes.Among them, lysine histone demethylase (KDM) can modify chromatin, that is, catalytic DNA binding histone 3 (DNA-binding histone 3, H3) lysine residue (lysine amino-acid residue, termed K9) demethylation. Closely related are KDM4A and KDM4B. Methylation of H3K9 is linked to the pathway of homology-dependent repair (HDR) and can be used to repair DNA double strand fractures (double-strands, DSBs), the most dangerous type of DNA damage.Sulkowski et al. found that tumor metabolites inhibit the HDR pathway, while confirming that KDM4A and KDM4B are critical to DSB repair, and found that HDR involves sequences of multiple repair factors recruited to DSB locations, where the Tip60 protein is the first protein to reach the damaged area, and ATM is the key protein needed for DNA repair. To dig deeper, they used a system that allows in-body cultured human cells to accurately initiate DSBs and monitor the repair process.By studying HDR in in-body cultured human cancer cells, it was found that at the DSB bit, H3K9 locally added three methylated H3K9me3 residues to produce triple methylation, which played a key role in the initial process of HDR. In addition, high levels of tumor metabolites inhibited KDM4B in tumor cells where the genes that encode IDH1, IDH2, Yanhuso acid hydrase, or amber acid dehydrogenase mutate. These results show that demethylation inhibition leads to extensive H3K9 high methylation, masking the appearance of specific local parts of the H3K9me3 marker and impairing the collection of the factors required for HDR and DSB repair.In addition, tumor metabolites not only inhibit hdR pathways, but are also highly sensitive to ADP-ribose polymerase (POLY(ADP-ribose) polymerase (PARP) inhibitors that are undergoing clinical trials. PARP enzymes promote the repair of single-stranded DNA fractures, blocking PARP inhibitors are used to treat certain types of cancer, while exploring the mechanisms by which tumor metabolites inhibit HDR can help provide effective treatment strategies for tumors caused by metabolite accumulation.
(Biological Exploration)