A thermophilic 8-oxoguanine DNA glycosylase from <italic>Thermococcus barophilus</italic>s Ch5 is a new member of AGOG DNA glycosylase family

Abstract

8-Oxoguanine (8oxoG) in DNA is a major oxidized base that poses a severe threat to genome stability. To counteract the mutagenic effect generated by 8oxoG in DNA, cells have evolved 8oxoG DNA glycosylase (OGG) that can excise this oxidized base from DNA. Currently, OGG enzymes have been divided into three families: OGG1, OGG2 and AGOG (archaeal 8oxoG DNA glycosylase). Due to the limited reports, our understanding on AGOG enzymes remains incomplete. Herein, we present evidence that an AGOG from the hyperthermophilic euryarchaeon Thermo Coccus barophilus Ch5 (Tb-AGOG) excises 8oxoG from DNA at high temperature. The enzyme displays maximum efficiency at 75°C–95°C and at pH 9.0. As expected, Tb-AGOG is a bifunctional glycosylase that harbors glycosylase activity and AP (apurinic/apyrimidinic) lyase activity. Importantly, we reveal for the first time that residue D41 in Tb-AGOG is essential for 8oxoG excision and intermediate formation, but not essential for DNA binding or AP cleavage. Furthermore, residue E79 in Tb-AGOG is essential for 8oxoG excision and intermediate formation, and is partially involved in DNA binding and AP cleavage, which has not been described among the reported AGOG members to date. Overall, our work provides new insights into catalytic mechanism of AGOG enzymes.

8-Oxoguanine DNA glycosylase protects cells from senescence via the p53-p21 pathway

“…We have previously reported that OGG1 inhibits the generation of ROS, alleviates mitochondrial dysfunction, and increases the expression of IL-1β induced by particulate matter [42] . OGG1 deficiency leads to a reduction in pulmonary fibrosis development, and the mechanism is partly based on the promotion of the TGF/Smad signaling pathway by OGG1, which aggravates the development of pulmonary fibrosis [15] . Aging can lead to a reduction in lung stem cells, mitochondrial dysfunction, oxidative stress damage and telomerase shortening, and ultimately leads to the inability of lung cells to maintain homeostasis, which plays important roles in the occurrence and development of IPF, chronic obstructive pulmonary disease and other pulmonary diseases [16] .…”