DNA mismatch repair and DNA damage response proteins (MMR/DDR proteins)

DNA mismatch repair (MMR) and DNA damage response (DDR) proteins are essential components of the cellular machinery that maintains genomic stability [1]. The MMR system specifically identifies and repairs erroneous insertion, deletion, and mis-incorporation of bases that occur during DNA replication and recombination [2]. The broader DDR network encompasses a variety of pathways, including base excision repair, nucleotide excision repair, and double-strand break repair, coordinated by sensors like ATM and ATR [1][3]. Mutations in these proteins, such as MLH1 or MSH2, are frequently associated with hereditary cancer syndromes like Lynch syndrome and a high degree of microsatellite instability [4]. In oncology, these proteins are significant therapeutic targets; for instance, PARP inhibitors exploit the concept of synthetic lethality in tumors with existing homologous recombination deficiencies [5]. Beyond PARP, inhibitors of ATR, ATM, and DNA-PK are currently being investigated to sensitize tumors to chemotherapy and radiation [6]. Understanding the interplay between these repair pathways is crucial for developing personalized medicine approaches based on a patient's specific genetic repair profile [1]. Consequently, these proteins serve as both critical therapeutic targets and vital biomarkers for predicting treatment response in various malignancies [5].

Other names

DNA repair proteinsGenome stability proteinsMMR proteinsDDR proteinsDNA repair machinery

Drugs targeting these proteins primarily act by inhibiting specific enzymatic activities (e.g., PARP, ATR, or ATM) to prevent the repair of DNA lesions. This often leads to the accumulation of lethal DNA damage, particularly in cancer cells that already possess primary defects in alternative repair pathways, a concept known as synthetic lethality [3][5]. Additionally, these inhibitors can be used to sensitize tumor cells to exogenous DNA-damaging agents like chemotherapy or radiation [6].