Two-Step Validation Approach for Tools To Study the DNA Repair Enzyme SNM1A.

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

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

Afiliación

Fay EM; School of Chemistry and Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, D02 R590, Ireland.
Newton A; School of Chemistry and Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, D02 R590, Ireland.
Berney M; School of Chemistry and Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, D02 R590, Ireland.
El-Sagheer AH; Department of Chemistry, University of Oxford, Mansfield Road, OX1 3TA, Oxford, UK.
Brown T; Department of Chemistry, University of Oxford, Mansfield Road, OX1 3TA, Oxford, UK.
McGouran JF; School of Chemistry and Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, Dublin 2, D02 R590, Ireland.

Chembiochem ; 24(13): e202200756, 2023 07 03.

Article en En | MEDLINE | ID: mdl-36917742

RESUMEN

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.

Asunto(s)

Proteínas de Ciclo Celular; Exodesoxirribonucleasas; Exodesoxirribonucleasas/metabolismo; Enzimas Reparadoras del ADN/química; Enzimas Reparadoras del ADN/metabolismo; Reparación del ADN; Oligonucleótidos/química

Palabras clave

DNA repair; SNM1A; fragment-based screening; metal-binding groups; oligonucleotide modification

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Ciclo Celular / Exodesoxirribonucleasas Idioma: En Revista: Chembiochem Asunto de la revista: BIOQUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Irlanda Pais de publicación: Alemania

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