Abstract
Constitutive heterochromatin is important for maintaining chromosome stability but also delays the repair of DNA double strand breaks (DSB). DSB repair in complex mammalian genomes involves a fast phase (2–6 hrs) where most of the breaks are rapidly repaired, and a slow phase (up to 24 hrs) where the remaining damages in heterochromatin are repaired. We found that p53 deficiency delays the slow phase DNA repair after ionizing irradiation. P53 deficiency prevents down regulation of histone H3K9 trimethylation at pericentric heterochromatin after DNA damage. Moreover, p53 directly induces expression of the H3 K9 demethylase JMJD2b through promoter binding. P53 activation also indirectly down regulates expression of the H3 K9 methytransferase SUV39H1. Depletion of JMJD2b or sustained expression of SUV39H1 delays the repair of heterochromatin DNA and reduces clonogenic survival after ionizing irradiation. The results suggest that by regulating JMJD2b and SUV39H1 expression, p53 not only controls transcription but also promotes heterochromatin relaxation to accelerate a rate-limiting step in the repair of complex genomes.
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