DNA-3-methyladenine glycosylase (MPG)

DNA-3-methyladenine glycosylase, commonly known as MPG or AAG, is a versatile enzyme that initiates the base excision repair (BER) pathway by recognizing and removing a wide range of damaged purine bases from DNA. Its primary substrates include 3-methyladenine, 7-methylguanine, hypoxanthine, and 1,N6-ethenoadenine, which are generated through alkylation, deamination, or oxidative stress. By excising these lesions, MPG plays a vital role in maintaining genomic integrity and preventing mutations. However, in the context of oncology, elevated MPG expression is often associated with resistance to alkylating chemotherapeutic agents like temozolomide, as the enzyme efficiently repairs the drug-induced DNA damage. Conversely, dysregulated MPG activity can lead to an accumulation of toxic abasic (AP) sites, which are mutagenic and can cause cell death. Consequently, MPG is a significant therapeutic target for cancer sensitization, where its pharmacological inhibition is being explored to enhance the efficacy of DNA-damaging therapies in resistant tumors such as glioblastoma.

Other names

Alkyladenine DNA glycosylaseAAGN-methylpurine DNA glycosylaseANPGADPGAPNG3-alkyladenine DNA glycosylaseMDGMid1PIG11PIG16

Inhibition of DNA-3-methyladenine glycosylase activity prevents the removal of cytotoxic DNA lesions (such as 3-methyladenine), leading to replication fork stalling and cell death, thereby sensitizing cancer cells to alkylating chemotherapeutic agents. Alternatively, drugs like methoxyamine bind to the abasic (AP) site product of the enzyme, blocking further repair and creating toxic intermediates.