Engineered chromatin readers track damaged chromatin dynamics in live cells and animals

Richard Cardoso da Silva (), Kristeli Eleftheriou, Davide C. Recchia, Vincent Portegijs, Douwe ten Bulte, Niklas Kupfer, Nathalie P. Vroegindeweij- de Wagenaar, Xabier Vergara, Ayoub Ouchene, Sander van den Heuvel and Tuncay Baubec ()
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Richard Cardoso da Silva: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology
Kristeli Eleftheriou: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology
Davide C. Recchia: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology
Vincent Portegijs: Utrecht University, Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology
Douwe ten Bulte: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology
Niklas Kupfer: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology
Nathalie P. Vroegindeweij- de Wagenaar: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology
Xabier Vergara: Netherlands Cancer Institute, Division of Gene Regulation
Ayoub Ouchene: Netherlands Cancer Institute, Division of Gene Regulation
Sander van den Heuvel: Utrecht University, Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology
Tuncay Baubec: Utrecht University, Genome Biology and Epigenetics, Institute of Biodynamics and Biocomplexity, Department of Biology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract DNA damage is a constant threat to genome integrity and function. Diminished capacity for DNA repair is linked to many human diseases, therefore, understanding the molecular pathways responding to DNA damage is key for developing novel therapies. Lack of unbiased probes to report DNA damage dynamics in living cells and animals limits our current efforts to completely understand DNA repair processes. In this study, we overcome these limitations by engineering protein probes containing the tandem-BRCT domain of MCPH1, which we show to have a specific affinity for the DNA-damage-associated histone mark γH2AX. We employ these probes to track DNA damage dynamics in living cells exposed to a panel of different genotoxic insults, to visualize DNA damage targeted to heterochromatinised satellite repeats, and to map DNA double strand breaks genome-wide. Finally, we highlight the versatility of our probe to visualize programmed double strand breaks during gametogenesis in C. elegans. Taken together, we present a novel protein probe with broad application potential for DNA damage research.

Date: 2025
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DOI: 10.1038/s41467-025-65706-y

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