Abstract

The exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a highly cytotoxic form of DNA damage.[1] As cells depleted in this enzyme show increased sensitivity to certain chemotherapeutic agents,[2] SNM1A is a potential target for treating cancers that have developed resistance to traditional chemotherapeutics. However, SNM1A and other enzymes of this class are poorly understood as there is a lack of tools available to facilitate their study.The active site of SNM1A contains two metal ions that are key to its catalytic activity. We report a two-step validation approach to evaluate the suitability of metal-binding groups for targeting the active site of SNM1A.[3] A fragment-based screening approach was first used to identify metal-binding fragments suitable for targeting the enzyme. Effective fragments were then incorporated into oligonucleotides via the CuAAC reaction. These modified oligonucleotides were recognised by SNM1A at >1000 fold lower concentrations than their fragment counterparts. Our novel approach of incorporating functional fragments into oligonucleotides is broadly applicable to generate modified oligonucleotide structures with high affinity for DNA damage repair enzymes. References:[1] E. M. Tacconi, S. Badie, G. De Gregoriis, T. Reisländer, X. Lai, M. Porru, C. Folio, J. Moore, A. Kopp, J. B. Torres, EMBO Mol. Med. 2019, 11.[2] A. T. Wang, B. Sengerová, E. Cattell, T. Inagawa, J. M. Hartley, K. Kiakos, N. A. Burgess-Brown, L. P. Swift, J. H. Enzlin, C. J. Schofield, Genes Dev. 2011, 25, 1859-1870.[3] E. Fay, A. Newton, M. Berney, A. El-Sagheer, T. Brown, J. F. McGouran, ChemBioChem, e202200756.