title: p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression.
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.
authors: Molecular Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: H
authors: H
authors: Zheng
authors: Molecular Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: L
authors: L
authors: Chen
authors: Molecular Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: W J
authors: WJ
authors: Pledger
authors: Molecular Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: J
authors: J
authors: Fang
authors: Molecular Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
authors: J
authors: J
authors: Chen
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D045325:HCT116 Cells; D006570:Heterochromatin / Q000235:genetics*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D008780:Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D006570:Heterochromatin; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C407843:SUV39H1 protein, human; D008780:Methyltransferases
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