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Florian Frohns, Steffen C Naumann, Paul G Layer, Markus Löbrich; Inefficient repair of DNA double-strand breaks in murine rod photoreceptors with highly heterochromatic DNA. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4382.
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DNA double-strand break (DSB) repair is a crucial process for the maintenance of genomic stability after exposure to ionizing radiation (IR) and other exogenous agents. Recent studies indicate cell type-specific differences in the response to DSBs, with chromatin organization representing one important factor influencing DSB repair. Here, we investigated the process of DSB repair in the mouse retina with its few distinct cell types and unique chromatin organization of its rod photoreceptors.
Postnatal and adult mice were irradiated in vivo with X-rays, using a dose of 1Gy. DSB repair was analyzed in specific cell types, including rod and cone-photoreceptors by quantification of radiation-induced γH2AX foci at various time points after treatment. The results were compared with data of retinae from ATM- and DNA-PK knockout mice, which show severe DNA damage repair defects within all cell types of their body. Differences in the composition of heterochromatin between postnatal and adult rod photoreceptors were analyzed by Western Blot.
Our studies revealed that adult rod photoreceptor cells of mice fail to repair 50% of the induced DSBs in a timely manner. This pronounced repair defect is neither observed in any other cell type of adult mice, nor in rod photoreceptor precursor cells of postnatal (P4) mice. Noticeably, this defect resembles closely that found in all cell types of ATM-knockout mice. However, the reason for this defect appears not to be a lack of ATM itself, but rather a missing phosphorylation of its substrate KAP1, which has previously been shown to relax heterochromatin and promote DSB repair.
Here, we describe that mouse rod photoreceptors exhibit an exquisite DSB repair defect, which has several important implications. First, the mouse retina often serves as a model system for studying human retinal degeneration. Since such studies involve exposure of retinal cells to DNA damaging agents, e.g. N-methyl-N-nitroso urea (MNU), the observed DSB signaling and repair defect might compromise the suitability of mouse rod cells as a model system for human retinal diseases. Second, the unique chromatin structure of mice rod photoreceptors represents an ideal model system for studying DSB signaling and repair in heterochromatic DNA regions.
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