DNA crosslinks are a highly cytotoxic form of DNA damage. DNA damage repair enzymes play a vital role in the repair of such DNA lesions. DNA crosslinking is exploited by some anti-cancer chemotherapeutics and therefore, inhibition of DNA repair enzymes could improve the success of such drugs.

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The 5’-3’ exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a cytotoxic form of DNA damage. It digests past DNA lesions with 5’-3’ directionality by hydrolysing the phosphodiester backbone. Due its implication in resistance to anti-cancer therapeutics, SNM1A is a potential target for anti-cancer chemotherapy and it is, therefore, important to fully understand its mechanism of action.

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Research in the group focuses on the synthesis of inhibitors and activity-based probes for poorly characterised nucleases such as SNM1A. These inhibitors are based on DNA, the natural substrate of SNM1A, and are synthesised through modification of nucleosides and nucleotides. Activity of the enzyme depends on metal ions in the active site, and hence, our research approach focuses on the incorporation of metal binding groups onto nucleosides and nucleotides. To date, we have successfully generated effective inhibitors for SNM1A based both on mononucleosides and oligonucleotides bearing various metal binding groups. Effective inhibitors have the potential to be developed into activity-based probes through incorporation of probe elements such as photocrosslinking groups and affinity handles.