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Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization.

Frohns, Antonia and Frohns, Florian and Naumann, Steffen C. and Layer, Paul G. and Löbrich, Markus :
Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization.
In: Current biology : CB, 24 (10) pp. 1080-1090. ISSN 1879-0445
[Article] , (2014)

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.

Item Type: Article
Erschienen: 2014
Creators: Frohns, Antonia and Frohns, Florian and Naumann, Steffen C. and Layer, Paul G. and Löbrich, Markus
Title: Inefficient Double-Strand Break Repair in Murine Rod Photoreceptors with Inverted Heterochromatin Organization.
Language: English
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.

Journal or Publication Title: Current biology : CB
Volume: 24
Number: 10
Divisions: 10 Department of Biology
10 Department of Biology > Developmental Biology and Neurogenetics
10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 13 May 2014 11:51
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