Two-step validation approach for tools to study the DNA repair enzyme SNM1A
Two-step validation approach for tools to study the DNA repair enzyme SNM1A
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.
DNA repair, SNM1A, fragment-based screening, metal-binding groups, oligonucleotide modification
Fay, Ellen M.
69871858-d66c-494b-b379-9b2153f06ce7
Newton, Ailish
17c4e2d1-b3eb-43e9-ac59-e76d24a5dd48
Berney, Mark
3031e490-eda8-4b54-8257-13fa3023b492
El-Sagheer, Afaf
05b8295a-64ad-4fdf-ad57-c34934a46c04
Brown, Tom
b8289de9-e08d-417f-b163-bcc9d7f34a71
McGouran, Joanna F.
0ddd7d98-49db-414a-89df-6a742a5afbde
3 July 2023
Fay, Ellen M.
69871858-d66c-494b-b379-9b2153f06ce7
Newton, Ailish
17c4e2d1-b3eb-43e9-ac59-e76d24a5dd48
Berney, Mark
3031e490-eda8-4b54-8257-13fa3023b492
El-Sagheer, Afaf
05b8295a-64ad-4fdf-ad57-c34934a46c04
Brown, Tom
b8289de9-e08d-417f-b163-bcc9d7f34a71
McGouran, Joanna F.
0ddd7d98-49db-414a-89df-6a742a5afbde
Fay, Ellen M., Newton, Ailish, Berney, Mark, El-Sagheer, Afaf, Brown, Tom and McGouran, Joanna F.
(2023)
Two-step validation approach for tools to study the DNA repair enzyme SNM1A.
ChemBioChem, 24 (13), [e202200756].
(doi:10.1002/cbic.202200756).
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.
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More information
Accepted/In Press date: 14 March 2023
e-pub ahead of print date: 2 June 2023
Published date: 3 July 2023
Additional Information:
Funding Information:
This work was supported by the Irish Research Council (GOIPG/2019/4189) and the Welcome Trust Trinity College Dublin (TCD) institutional strategic support fund. Open Access funding provided by IReL.
Publisher Copyright:
© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.
Keywords:
DNA repair, SNM1A, fragment-based screening, metal-binding groups, oligonucleotide modification
Identifiers
Local EPrints ID: 478390
URI: http://eprints.soton.ac.uk/id/eprint/478390
ISSN: 1439-4227
PURE UUID: c0e4eace-166a-43d6-9f1a-626dacb03c49
Catalogue record
Date deposited: 29 Jun 2023 16:53
Last modified: 17 Mar 2024 03:04
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Contributors
Author:
Ellen M. Fay
Author:
Ailish Newton
Author:
Mark Berney
Author:
Afaf El-Sagheer
Author:
Tom Brown
Author:
Joanna F. McGouran
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