Editors' ChoiceDNA Damage Response

Repair and Protect

Science Signaling  08 Feb 2011:
Vol. 4, Issue 159, pp. ec35
DOI: 10.1126/scisignal.4159ec35

Mutations that compromise the activity of the kinase ATM cause ataxia telangiectasia (A-T), symptoms of which include susceptibility to cancer, immunodeficiency, and neurological defects. Noting that cerebellar neurons of mice deficient in ATM exhibit low amounts of NADPH, which is a required cofactor for many antioxidant enzymes, and that human A-T lymphoblasts recover from glutathione depletion more slowly than do wild-type cells, Cosentino et al. used cultured mammalian cells and Xenopus egg extracts to investigate whether there was a connection between ATM activity and the pentose phosphate pathway (PPP), which produces NADPH [through the activity of glucose-6-phosphate dehydrogenase (G6PD)] and nucleotides. The addition of DNA with double-stranded breaks (DSBs) to the Xenopus extract system, which lacks transcriptional machinery, or irradiation of cultured human cells caused an increase in G6PD activity and NADPH production that was prevented by inhibition of ATM activity. Addition of DSBs to the Xenopus extract or irradiation of human cultured cells stimulated the ATM-dependent phosphorylation and interaction of heat shock protein 27 (Hsp27), a known stimulator of G6PD activity, with G6PD. Activation of G6PD by irradiation was prevented by knockdown of Hsp27. Cells or extracts deficient in G6PD exhibited reduced DNA repair and increased production of reactive oxygen species (ROS). Biochemical analysis of the incorporation of labeled PPP intermediates into RNA in irradiated human lymphoblasts showed increased metabolic flux through the PPP. This research not only provides a potential explanation for the high amount of oxidative damage and reduced antioxidant capacity of cerebellar neurons in A-T patients but also connects ATM to a metabolic pathway critical for DNA repair and maintenance of oxidative balance.

C. Cosentino, D. Grieco, V. Costanzo, ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J. 30, 546–555 (2011). [PubMed]