p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression

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.

Kdm4b Histone Demethylase Is a DNA Damage Response Protein and Confers a Survival Advantage following γ-Irradiation

“…Moreover, we demonstrated that despite reduced DBS repair, as assayed by ␥H2AX foci, the Suv39h1/h2-dn cells display an increased tolerance to ␥-irradiation-induced DNA damage. This is consistent with a recent report by Zheng et al (60) demonstrating that overexpression of Suv39h1 increased sensitivity to ␥-irradiation. Taking into account the increased genomic instability and tumor-prone phenotype associated with Suv39h1/h2 deficiency (16 -18), it is possible that reductions in H3K9me3 confer an increased tolerance to DNA damage.…”

Nucleolar Reorganization Upon Site-Specific Double-Strand Break Induction

“…11,50,51 Nucleolus itself is a good example of how transcription, chromatin remodeling, and DNA repair might go together. Cockayne syndrome B (CSB) protein is a DDR factor involved in the early steps of transcriptioncoupled NER that is also important in the regulation of rRNA gene expression.…”

The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression

“…Inhibition of mTOR using rapamycin blocks senescence and keeps cells in a state of reversible quiescence after p21 overexpression (Demidenko et al 2009). p53 also represses the expression of histone H3K9 methylase SUV39H1 and induces histone demethylase JMJD2d, which may prevent the establishment of stable gene silencing (Zheng et al 2013). Therefore, cellular context and pathway cross talk may determine whether cells commit to irreversible cell-cycle arrest.…”

“…Furthermore, p53 regulates genes involved in heterochromatin formation to facilitate the timely repair of DNA strand breaks in constitutive heterochromatin regions. p53-null cells have deficiencies in the repair of doublestrand breaks in heterochromatin and have reduced long-term viability after ionizing irradiation (Zheng et al 2013).…”