Sirtuin-mediated DNA damage response by modulation of glutamate dehydrogenase activity in Arabidopsis thaliana

Sirtuins, ClassIII NAD-dependent deacetylases, play a central role in many metabolic pathways related to cell survival and are evolutionary conserved from bacteria to mammals. Among the seven human sirtuins, SIRT4 and SIRT6 share homology domains with the two sirtuins present in Arabidopsis thaliana plants, AtSRT2 and AtSRT1 respectively. With the aim to evaluate sirtuin functions in phylogenetically distant organisms, we report data on a corresponding role between Arabidopsis SRT2 and human SIRT4 genes. We find that AtSRT2 is involved in a defence process already known to be regulated by SIRT4. In fact the DNA Damage Response (DDR) in human cells induces SIRT4 that in turn limits proliferation via repression of glutamine metabolism (Jeong et al, Cancer Cell 2013, 23:450). In Arabidopsis seedlings, the induction of DNA damage promotes transcriptional activation of SRT2 gene and decreased activity of glutamate dehydrogenase (GDH), one of the enzymes that catalyze a-ketoglurate (aKG) production from glutamine. As aKG is a major anaplerotic component of TCA cycle in proliferating cells, the decreased GDH activity is coherent with the slowed cell proliferation that we observed. Moreover, in plants knock out for SRT2, GDH activity and cell proliferation are less affected by DNA damage, confirming the role of AtSRT2 in this metabolic pathway.