Two‐step validation approach for tools to study the DNA repair enzyme SNM1A

Ellen M. Fay, Ailish Newton, Mark Berney, Afaf H. El-Sagheer, Tom Brown, Joanna F. McGouran

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
1 Downloads (Pure)

Abstract

We report a two-step validation approach to evaluate the suitability of metal-binding groups for targeting DNA damage-repair metalloenzymes using model enzyme SNM1A. 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 using the copper-catalysed azide–alkyne cycloaddition reaction. These modified oligonucleotides were recognised by SNM1A at >1000-fold lower concentrations than their fragment counterparts. The exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a highly cytotoxic form of DNA damage. However, SNM1A and other enzymes of this class are poorly understood, as there is a lack of tools available to facilitate their study. Our novel approach of incorporating functional fragments into oligonucleotides is broadly applicable to generating modified oligonucleotide structures with high affinity for DNA damage-repair enzymes.
Original languageEnglish
Article numbere202200756
JournalChemBioChem
Volume24
Issue number13
Early online date02 Jun 2023
DOIs
Publication statusPublished - 03 Jul 2023
Externally publishedYes

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