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Differences in the Response to DNA Double-Strand Breaks between Rod Photoreceptors of Rodents, Pigs, and Humans

Frohns, Florian ; Frohns, Antonia ; Kramer, Johanna ; Meurer, Katharina ; Rohrer-Bley, Carla ; Solovei, Irina ; Hicks, David ; Layer, Paul G. ; Löbrich, Markus (2021):
Differences in the Response to DNA Double-Strand Breaks between Rod Photoreceptors of Rodents, Pigs, and Humans. (Publisher's Version)
In: Cells, 9 (4), MDPI, e-ISSN 2073-4409,
DOI: 10.26083/tuprints-00019030,
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Item Type: Article
Origin: Secondary publication service
Status: Publisher's Version
Title: Differences in the Response to DNA Double-Strand Breaks between Rod Photoreceptors of Rodents, Pigs, and Humans
Language: English
Abstract:

Genome editing (GE) represents a powerful approach to fight inherited blinding diseases in which the underlying mutations cause the degeneration of the light sensing photoreceptor cells of the retina. Successful GE requires the efficient repair of DNA double-stranded breaks (DSBs) generated during the treatment. Rod photoreceptors of adult mice have a highly specialized chromatin organization, do not efficiently express a variety of DSB response genes and repair DSBs very inefficiently. The DSB repair efficiency in rods of other species including humans is unknown. Here, we used ionizing radiation to analyze the DSB response in rods of various nocturnal and diurnal species, including genetically modified mice, pigs, and humans. We show that the inefficient repair of DSBs in adult mouse rods does not result from their specialized chromatin organization. Instead, the DSB repair efficiency in rods correlates with the level of Kruppel-associated protein-1 (KAP1) expression and its ataxia-telangiectasia mutated (ATM)-dependent phosphorylation. Strikingly, we detected robust KAP1 expression and phosphorylation only in human rods but not in rods of other diurnal species including pigs. Hence, our study provides important information about the uniqueness of the DSB response in human rods which needs to be considered when choosing model systems for the development of GE strategies.

Journal or Publication Title: Cells
Journal volume: 9
Number: 4
Publisher: MDPI
Collation: 16 Seiten
Classification DDC: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Divisions: 10 Department of Biology > Developmental Biology and Neurogenetics
10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 16 Aug 2021 12:21
Last Modified: 16 Aug 2021 12:21
DOI: 10.26083/tuprints-00019030
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-190302
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/19030
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