AP endonuclease deficiency results in extreme sensitivity to thymidine deprivation.

摘要: Thymidine depletion is toxic to virtually all actively growing cells. The fundamental mechanism responsible for thymidineless death remains unknown. One event thought be critical in causing the toxicity of thymidine a sharp rise ratio dUTP dTTP and subsequent incorporation into DNA. Maneuvers alter levels appear depletion. However, loss uracil-DNA-N-glycosylase activity does not change deprivation significantly. This study proposes define role uracil base excision repair (BER) mediating death. induced by antifolate aminopterin was measured series mutant Saccharomyces cerevisiae strains deficient various steps uracil-BER. Most mutants displayed modest changes their sensitivity aminopterin, with exception cells lacking abasic endonuclease Apn1. apn1 profound that relieved an ung1 double mutant. Wild-type similar DNA damage S-phase arrest during treatment. A significant portion cell killing occurred after removal both wild-type showed complete inability re-initiate replication following aminopterin. These findings suggest recovery from crucial step determining response interruptions uracil-BER increase blocking re-initiation rather than inciting global damage. Inhibition apurinic/apyrimidinic may therefore reasonable approach efficacy anticancer chemotherapies based on