1. Differences in the Response to DNA Double-Strand Breaks between Rod Photoreceptors of Rodents, Pigs, and Humans
- Author
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Irina Solovei, David Hicks, Johanna Kramer, Florian Frohns, Katharina Meurer, Markus Löbrich, Carla Rohrer-Bley, Paul G. Layer, and Antonia Frohns
- Subjects
0301 basic medicine ,retina ,DNA Repair ,genetic structures ,Swine ,DNA repair ,inherited retinal dystrophies ,Biology ,Article ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Genome editing ,Retinal Rod Photoreceptor Cells ,medicine ,genome editing ,Animals ,Humans ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,DNA Breaks, Double-Stranded ,lcsh:QH301-705.5 ,Gene ,Gene Editing ,Retina ,photoreceptors ,General Medicine ,Chromatin ,Cell biology ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,chemistry ,ATM ,KAP1 ,chromatin ,Phosphorylation ,sense organs ,CRISPR-Cas9 ,DNA double-stranded break ,030217 neurology & neurosurgery ,DNA - 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.
- Published
- 2020