Frohns, Antonia ; Frohns, Florian ; Naumann, Steffen C. ; Layer, Paul G. ; Löbrich, Markus (2014)
Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization.
In: Current biology : CB, 24 (10)
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
BACKGROUND
DNA double-strand break (DSB) repair is crucial for the maintenance of genomic stability, and chromatin organization represents one important factor influencing repair efficiency. Mouse rod photoreceptors with their inverted heterochromatin organization containing a single large chromocenter in the middle of the nucleus provide a unique model system to study DSB repair in heterochromatin of living animals.
RESULTS
We observed that adult rod photoreceptors repair only half of the induced DSBs within 1 day after damage induction, a defect that is neither observed in any other cell type of the adult retina nor in rod photoreceptor precursor cells of postnatal day 4 mice. We show that adult wild-type rods are deficient in a repair pathway involving ATM, a protein that promotes heterochromatic DSB repair by phosphorylating KAP1 and facilitating heterochromatin relaxation. Of note, we observed that rods fail to robustly accumulate active ATM at DSBs, exhibit low KAP1 levels, and display high levels of SPOC1, a factor suppressing KAP1 phosphorylation. Collectively, this results in dramatically reduced KAP1 phosphorylation and the inability to repair heterochromatic DSBs.
CONCLUSIONS
Because the distinct heterochromatic structure of rods focuses transmitting light to enable vision at low photon levels, the inability to phosphorylate KAP1 and the failure to relax heterochromatin could serve to maintain this structure and the functionality of rods in the presence of DSBs. Collectively, our findings show that the unique chromatin organization of adult rods renders them incapable to efficiently repair heterochromatic DSBs, providing evidence that heterochromatin affects mammalian DSB repair in vivo.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2014 |
| Autor(en): | Frohns, Antonia ; Frohns, Florian ; Naumann, Steffen C. ; Layer, Paul G. ; Löbrich, Markus |
| Art des Eintrags: | Bibliographie |
| Titel: | Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization. |
| Sprache: | Englisch |
| Publikationsjahr: | 2014 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Current biology : CB |
| Jahrgang/Volume einer Zeitschrift: | 24 |
| (Heft-)Nummer: | 10 |
| Kurzbeschreibung (Abstract): | BACKGROUND DNA double-strand break (DSB) repair is crucial for the maintenance of genomic stability, and chromatin organization represents one important factor influencing repair efficiency. Mouse rod photoreceptors with their inverted heterochromatin organization containing a single large chromocenter in the middle of the nucleus provide a unique model system to study DSB repair in heterochromatin of living animals. RESULTS We observed that adult rod photoreceptors repair only half of the induced DSBs within 1 day after damage induction, a defect that is neither observed in any other cell type of the adult retina nor in rod photoreceptor precursor cells of postnatal day 4 mice. We show that adult wild-type rods are deficient in a repair pathway involving ATM, a protein that promotes heterochromatic DSB repair by phosphorylating KAP1 and facilitating heterochromatin relaxation. Of note, we observed that rods fail to robustly accumulate active ATM at DSBs, exhibit low KAP1 levels, and display high levels of SPOC1, a factor suppressing KAP1 phosphorylation. Collectively, this results in dramatically reduced KAP1 phosphorylation and the inability to repair heterochromatic DSBs. CONCLUSIONS Because the distinct heterochromatic structure of rods focuses transmitting light to enable vision at low photon levels, the inability to phosphorylate KAP1 and the failure to relax heterochromatin could serve to maintain this structure and the functionality of rods in the presence of DSBs. Collectively, our findings show that the unique chromatin organization of adult rods renders them incapable to efficiently repair heterochromatic DSBs, providing evidence that heterochromatin affects mammalian DSB repair in vivo. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Developmental Biology and Neurogenetics 10 Fachbereich Biologie > Radiation Biology and DNA Repair |
| Hinterlegungsdatum: | 13 Mai 2014 11:51 |
| Letzte Änderung: | 24 Jun 2014 11:54 |
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