title: Inefficient double-strand break repair in murine rod photoreceptors with inverted heterochromatin organization.
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.
authors.affiliation: Darmstadt University of Technology, Radiation Biology and DNA Repair, 64287 Darmstadt, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Frohns
authors.affiliation: Darmstadt University of Technology, Developmental Biology and Neurogenetics, 64287 Darmstadt, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Frohns
authors.affiliation: Darmstadt University of Technology, Radiation Biology and DNA Repair, 64287 Darmstadt, Germany.
authors.forename: Steffen C
authors.initials: SC
authors.lastname: Naumann
authors.affiliation: Darmstadt University of Technology, Developmental Biology and Neurogenetics, 64287 Darmstadt, Germany.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Layer
authors.affiliation: Darmstadt University of Technology, Radiation Biology and DNA Repair, 64287 Darmstadt, Germany. Electronic address: lobrich@bio.tu-darmstadt.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Löbrich
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins; D006570:Heterochromatin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063146:Polycomb-Group Proteins; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D006570:Heterochromatin; C533390:Phf1 protein, mouse; D063146:Polycomb-Group Proteins; D014157:Transcription Factors; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse