Nature: Tumor metabolites hinder DNA repair! The reason is that local chromosome signals are disturbed!

June 5, 2020 /
BiovalleyBIOON/- Chromosomal abnormalities detected in the light mirror at the end of the 19th century revealed a massive genomic instability that caused abnormal chromosome numbers for certain types of cancerSoon after, biochemist Otto Warburg observed that tumor cells tend edgtoser pathways of glucose and energy metabolism that are different from normal cellsWe now know that genomic instability and metabolic changes are two common characteristics of most tumor cellsGenomic instability has been studied since its discovery; metabolic changes have only recently been rediscovered as a field of researchBut so far, the interaction between the two processes in cancer treatment has not been reportedIn an article published June 4 in the journal Nature, Sulkowski et alrevealed how several metabolites that accumulate at high levels ofcells intumors inhibit DNA repair, revealing a direct link between metabolic changes and genomic instability caused by DNA damagepicture source: Nature
mutations in genes that encode isocitric acid dehydrogenase 1 and 2 (IDH1 and IDH2) cause cells to accumulate high levels of metabolites 2-hydroxyprene (2-HG)Mutations in the genes that encode Yanhuso acid hydration enzyme and succinic dehydrogenase resulted in high levels of yanhuso acid and succinic acid molecules accumulated by cells, respectivelyThese three small molecules are commonly referred to as tumor metabolites because their accumulation promotes the development oftumor, which are structurally similar to the molecular alpha-ketone diacid (alpha-KG)This is an intermediate product in the Krebs circulatory pathway, also as a component called a common substrate, a class of substances called alpha-KG/Fe(II) that rely on the form of dioxyasethis enzyme family consists of 65 members that catalyze a variety of oxidation reactions in proteins, DNA, RNA and lipidsIn these reactions, alpha-KG binds to the active part of the enzyme and is catalyzedHowever, 2-HG, succinic acid, and yanhuso acid can compete with alpha-KG to bind to this catalytic site, thereby inhibiting these enzymesOne of these enzymes is lysine histone demethylase (KDM), which modifies chromatin -- a compound madeby DNA andproteomicstwo closely related KDMs, called KDM4A and KDM4B, catalyzed the removal of methyl (demethylation) from the residual squiteen amino acid residue (called K9) in DNA binding to histone 3 (H3) in chromatinMethylation of H3K9 is associated with a pathway called homologous remediation (HDR), which can repair double-stranded fractures (DSBs) in DNA8DSBs are the most dangerous type of DNA damageIf left unrepaired, they can lead to chromosomal fractures and genomic instability, which may promote the growth oftumorsor cause cell deathSulkowski and colleagues studied HDR in in vitro cultured human cancer cellsThey found that at the DSB site, H3K9 locally added three methyls, generating trimethylated H3K9me3 residues, which played a key role in the initial HDR process The authors report that high levels of tumor
metabolites inhibit KDM4B in tumor cells that mutate the genes that encode IDH1, IDH2, Yanhuiso acid hydration enzyme, or succinic dehydrogenase This demethylation inhibition led to extensive H3K9 high methylation, masking the presence of specific localized h3K9me3 markers, and undermining the collection of factors required for HDR and DSB repair previous clinical studies have found that patients with a cancer called glioma and a mutation in the IDH1 or IDH2 gene can benefit from a combination of chemotherapy and radiotherapy, both of which can lead to DNA damage The findings suggest that if the tumor in the tumor metabolites are too high, it is vulnerable to THE treatment of DNA damage In addition, genomic analysis of different types of cancer ranks IDH1 as the fifth most frequently mutated human gene associated with DNA repair previous researchers have proposed two mechanisms to explain how the accumulation of 2-HG causes DNA repair defects when a mutation occurs in IDH1 or IDH2 One idea is that 2-HG directly inhibits enzymes ALKBH2 and ALKBH3, both of which repair methylation-induced single-stranddna damage Another theory is that 2 HG inhibits H3K9 demethylase, which leads to reduced expression of ATM, the key protein necessary for DNA repair Sulkowski and his colleagues have previously found that single metabolites inhibit HDR pathways and identified KDM4A and KDM4B as important for DSB repair Therefore, the author explores the possible links between these processes HDR is a complex event involving multiple repair factor sequences recruited to the DSB site, where the protein Tip60 is the first protein to reach the damaged area Sulkowski et al used a system in which in vitro cultured human cells were designed to precisely start the DSB and monitor the repair process the authors found that in control cells without high levels of tumor metabolites, peaks of H3K9me3 modification appeared rapidly in chromatin near DSB within 30 minutes of DSB induction Subsequently, the factors required for HDR were coordinated However, in cancer cells with high levels of tumor
metabolites, H3K9me3 increased throughout the genome prior to DSB induction, and subsequently HDR factors were significantly damaged compared to control cells By removing the mutational version of IDH1 or using a pharmacological inhibitor of the mutant IDH1 protein to block the production of 2-HG can prevent defects in these repair factor supplements These results establish a causal relationship between the presence of a single metabolite and the repair of damaged DSB picture source: How does Nature tumor metabolites inhibiting KDM4B damage HDR? Local H3K9 methylation activates Tip60, which in turn activates ATM, which is the key enzyme required for HDR The results of a series of experiments support the author's model that a sudden increase in H3K9me3 modification at the DSB site is a key signal for recruiting repair factors Preventing the accumulation of tumor metabolites, increasing alpha-KG or engineering cell expression KDM4A or KDM4B (but excluding other KDMs or ALKBH2/ALKBH3) will reduce whole genome H3K9me3 modification, restore damage repair factor recruitment, and DNA damage to the site of DSB repair If the cells that produce tumor metabolites are manipulated to mutate H3K9 methyl metastase mutations, thereby reducing H3K9me3 modification at genomic levels, then the cells will experience a spike in H3K9me3 during the DSB process, leading to Tip60 recruitment and repair of DNA damage The findings of Sulkowski and his colleagues extend the known role of monometabolics and raise several interesting questions How did the rapid increase of H3K9me3 at the DSB site lead to co-raising of repair proteins? What factors might identify this modification of the DSB site? Does High Methylation of H3K9 prevent the binding of the factors required for HDR around the DSB site? High methylation of H3K9 is known to recruit inhibitors that promote the formation of a concentrated form of chromatin called isoched chromatin Questions remain about whether the roles of KDM4A and KDM4B are different in HDR The two enzymes catalyze the same type of H3K9 demethylation, promoting their expression can overcome the inhibition of tumor
metabolites and prevent HDR defects However, the authors report that KDM4B consumption only harms HDR PARP enzyme promotes the repair of single-stranddna DNA fractures and blocks PARP inhibitors used to treat certain types of cancer If treated with PARP inhibitors, tumor cells that produce 2-
HG are particularly likely to die The discovery of Sulkowski et al could lead to a new treatment strategy, the use of single metabolites to accumulate treatment opportunities, as we now have a clearer understanding of the vulnerability of such cancer cells during targeted DNA repair (biovalleybioon.com) References: 's Tumour-Trump-blites-sand-d.Dna repair
, P.L., Oeck, S., Dow, J et al.
Oncometabolites DNA suppress repair by disrupting local chromatin signalling Nature (2020) https://doi.org/10.1038/s41586-020-2363-0