Researchers reveal how tumor metabolites block DNA repair

Recently, the journal Nature revealed how several metabolites accumulated in tumor cells inhibited DNA repair mechanisms, pointing to a direct link between metabolic changes and genomic instability caused by DNA damageThe study was conducted by Sulkowski of Yale University School of Medicine and othersDoi: 10.1038/d41586-020-01569-1 isocrate dehydrogenase 1 and 2 (isocitrate dehydrogenase 1 and 2, IDH1 and IDH 2) genes cause a large accumulation of metabolites in the cell 2-hydroxyl diazenota (2-hydrocoglutarate, 2-HG)Genetic mutations in Fumarate hydrohydrate (fumarate hydratase, FH) and succinate dehydrogenase, SDHA, SDHB, SDHC and SDHD resultin in an increase in the molecular growth of Yanhuso acid and semacid acidThe accumulation of all three metabolites promotes tumor development and is therefore called tumor metabolites (oncometabolites)Alpha-ketone diacid (alpha-ketoglutarate, alpha-KG) is an intermediate product in the Krebs cycle path and is essential for the population of alpha-KG/Fe(II) dependent on the dioxidase familyThe family binds to the enzyme-active site through its alpha-KG, which in turn involves catalyzing oxidation reactions in proteins, DNA, RNA and lipidsThe three metabolites of 2-HG, yanhuso acid and succinic acid are structurally similar to alpha-KG, so they can compete with alpha-KG to bind to the catalytic site, thereby inhibiting these enzymesAmong other things, lysine histone demethylase (lysine histone demethylase, KDM) can modify chromatin, i.ecatalytic DNA binding histone 3 (DNA-binding histone 3, H3) lysine residuals (lysine amino-acid, termed K9) demethylatingClosely related are KDM4A and KDM4BMethylation of H3K9 is linked to homology-dependent repair (HDR) and can be used to repair DOUBLE-strand breaks (double-strand breaks, DSBs), the most dangerous type of DNA damageHow tumor metabolites inhibit DNA damage Repair Sulkowski et alHave found that tumor metabolites inhibit HDR pathways, while confirming that KDM4A and KDM4B are critical to DSB repair, and found that HDR involves the sequence of multiple repair factors being recruited to DSB sites, where Tip60 protein is the first protein to reach the damaged area, and ATM is also the key protein needed for DNA repairTo dig deeper, they used a system that allowed in vitro cultured human cells to accurately start the DSB and monitor the repair processTumor metabolites directly inhibit HDR by studying HDR in in vitro cultured human cancer cells and found that at the DSB site, H3K9 locally added 3 methyltors to produce trimethylated H3K9me3 residues, which play a key role in the initiation of HDRIn addition, high levels of tumor metaboliteinhibited KDM4B in tumor cells whose genes encoded IDH1, IDH2, Yanhuso acid hydrate, or semacid dehydrogenase were mutatedThese results show that demethylation inhibition leads to extensive H3K9 high methylation, masking the specific local appearance of H3K9me3 markers, and impairing the collection of factors required for HDR and DSB repairIn addition to DSBs in which tumor metabolites inhibit HDR factors into DNA, tumor metabolites not only inhibit the pathway of HDR, but are also highly sensitive to ADP-ribose polymerase (ADP-ribose) polymerase inhibitors in ongoing clinical trialsPARP enzymes promote the repair of single-stranded DNA fractures, block parP inhibitors are used to treat certain types of cancer, and exploring the mechanisms by which tumor metabolites inhibit HDR can help provide effective treatment strategies for tumors caused by metabolite accumulationRelated: s1 Saeach Tumour sanddna repair s2 oncometabolites suppress DNA repair by disrupting local chromatin signalling