title: p53-mediated heterochromatin reorganization regulates its cell fate decisions.
abstract: p53 is a major sensor of cellular stresses, and its activation influences cell fate decisions. We identified SUV39H1, a histone code 'writer' responsible for the histone H3 Lys9 trimethylation (H3K9me3) mark for 'closed' chromatin conformation, as a target of p53 repression. SUV39H1 downregulation was mediated transcriptionally by p21 and post-translationally by MDM2. The H3K9me3 repression mark was found to be associated with promoters of representative p53 target genes and was decreased upon p53 activation. Overexpression of SUV39H1 maintained higher levels of the H3K9me3 mark on these promoters and was associated with decreased p53 promoter occupancy and decreased transcriptional induction in response to p53. Conversely, SUV39H1 pre-silencing decreased H3K9me3 levels on these promoters and enhanced the p53 apoptotic response. These findings uncover a new layer of p53-mediated chromatin regulation through modulation of histone methylation at p53 target promoters.
authors.affiliation: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Sathish Kumar
authors.initials: SK
authors.lastname: Mungamuri
authors.forename: Erica Kay
authors.initials: EK
authors.lastname: Benson
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Aaronson
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005786:Gene Expression Regulation; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006570:Heterochromatin; D006657:Histones; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C407843:SUV39H1 protein, human; D008780:Methyltransferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2