Congratulations to Leonardo Serafim, co-author on a just published paper in the journal Nature Communications entitled “A unified catalytic mechanism in bifunctional DNA glycosylases with an evolutionarily conserved aspartate-lysine dyad”, a collaboration with John Tainer’s group at MD Anderson Cancer Center.
Bifunctional glycosylases, OGG1 for oxidized purines and NTH1 for oxidized pyrimidines, repair oxidatively damaged DNA bases through two consecutive reactions: removal of the damaged base and cleavage of the DNA backbone (the AP-lyase step). Combining crystal structures of archaeal and human OGG1 and NTH1, captured in damage-recognition and catalysis-ready states, with ab initio molecular dynamics simulations of their complete reaction pathways, we defined a single catalytic mechanism shared by both enzymes and conserved over three billion years of evolution. It differs from the oxocarbenium-ion mechanism of monofunctional glycosylases: ribose protonation and ring opening come before the base is cut free, and a conserved aspartate-lysine pair acting as an acid-base catalyst lowers the barrier for breaking the glycosidic bond.
Structures of human OGG1 bound to product DNA, with and without the small-molecule activator F51, show that such activators speed up the enzyme by helping it release its product. These results open a route to chemical tools for probing the lyase reaction and to therapeutics against oxidative DNA damage in cancer and aging.
Syed, A., Serafim, L. F., … Ivanov, I.* & Tainer, J. A.* Nature Communications 17, 8681 (2026).
