Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of O⁶-methylguanine and their recognition by MGMT and Atl1

Abstract

Promutagenic O 6-alkylguanine adducts in DNA are repaired in humans by O 6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O 6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic.

The Role of Autophagy in Gastric Cancer Chemoresistance: Friend or Foe?

“…O-6-methylguanine-DNA methyltransferase (MGMT) is a type of suicide DNA damage repair enzymes, and DNA damage repair disorders have been reported to induce autophagy (Balvers et al, 2015;Abdu et al, 2020). Lei et al (2020) have found that the high expression of MGMT is significantly correlated with the low expression of ATG4B and the favorable prognosis of gastric cancer.…”