Function and inhibition of the DNA repair enzyme SNM1A

SNM1A is an enzyme involved in several important biological pathways. To date, most investigations have focused on its role in repairing interstrand crosslinks, a highly cytotoxic form of DNA damage. SNM1A acts as a 5'-3' exonuclease, displaying an unusual capability to digest DNA past the site of a crosslink lesion. Recently, additional functions of this enzyme in the repair of DNA double-strand breaks and critically shortened telomeres have been uncovered. Furthermore, SNM1A is involved in two cell cycle checkpoints that arrest cell division in response to DNA damage. Inhibition of both DNA repair enzymes and cell cycle checkpoint proteins are effective strategies for cancer treatment, and SNM1A is therefore of significant interest as a potential therapeutic target. As a member of the metallo-β-lactamase superfamily, SNM1A is postulated to contain two metal ions in the active site that catalyse hydrolysis of the phosphodiester backbone of DNA. Substrate-mimic probes based on a nucleoside or oligonucleotide scaffold appended with a metal-binding group have proven effective in vitro. High-throughput screening campaigns have identified potent inhibitors, some of which were successful in sensitising cells to DNA-damaging cancer drugs. This review discusses the biological role, structure, and mechanism of action of SNM1A, and the development of SNM1A inhibitors for cancer therapy.