Abstract
Constitutive heterochromatin (HC) is important for maintaining chromosome stability, but also delays the repair of DNA double-strand breaks (DSBs). DSB repair in complex mammalian genomes involves a fast phase (2-6 h) in which most of the breaks are rapidly repaired, and a slow phase (up to 24 h) in which the remaining damages in HC are repaired. We found that p53 deficiency delays the slow-phase DNA repair after ionizing irradiation. p53 deficiency prevents downregulation of histone H3K9 trimethylation at the pericentric HC after DNA damage. Moreover, p53 directly induces expression of the H3K9 demethylase Jumonji domain 2 family demethylase (JMJD2b) through promoter binding. The p53 activation also indirectly downregulates expression of the H3K9 methyltransferase SUV39H1. Depletion of JMJD2b or sustained expression of SUV39H1 delays the repair of HC 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 HC relaxation to accelerate a rate-limiting step in the repair of complex genomes.