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Comment
. 2020 Jun;582(7813):492-494.
doi: 10.1038/d41586-020-01569-1.

Tumour metabolites hinder DNA repair

Lei-Lei Chen, Yue Xiong
Comment

Tumour metabolites hinder DNA repair

Lei-Lei Chen et al. Nature. 2020 Jun.
No abstract available

Keywords: Cancer; Metabolism.

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Figures

Figure 1 |
Figure 1 |. How molecules in cancer cells inhibit the repair of DNA damage.
a, DNA wraps around histone proteins to form a structure called a nucleosome. In normal cells, the enzyme KDM4B catalyses the removal of methyl groups from the lysine 9 (K9) amino-acid residue of the protein histone 3 (H3) in the nucleosome. This H3K9 demethylation activity requires the small molecule α-ketoglutarate (α-KG). If a double-strand break in DNA occurs, H3K9 is methylated at the damage site and this local methylation signal recruits DNA-repair factors that include the proteins Tip60 and ATM. These fix the damage through a process called homology-dependent repair. b, As a result of certain mutations, some cancer cells accumulate small molecules termed oncometabolites that promote tumour growth. Sulkowski et al. have revealed a mechanism that underlies this phenomenon. Oncometabolites compete with α-KG for binding to KDM4B and thus inhibit the enzyme’s function. This results in H3K9 methylation across the genome. This global hypermethylation masks a local spike in H3K9 methylation occurring after DNA damage, and hinders the recruitment of DNA-repair factors. Unrepaired DNA damage can lead to genome instability and thus boost tumour growth.
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