title: Ash2L enables P53-dependent apoptosis by favoring stable transcription pre-initiation complex formation on its pro-apoptotic target promoters.
abstract: Chromatin conformation has a major role in all cellular decisions. We showed previously that P53 pro-apoptotic target promoters are enriched with H3K9me3 mark and induction of P53 abrogates this repressive chromatin conformation by downregulating SUV39H1, the writer of this mark present on these promoters. In the present study, we demonstrate that in response to P53 stabilization, its pro-apoptotic target promoters become enriched with the H3K4me3 epigenetic mark as well as its readers, Wdr5, RbBP5 and Ash2L, which were not observed in response to SUV39H1 downregulation alone. Overexpression of Ash2L enhanced P53-dependent apoptosis in response to chemotherapy, associated with increased P53 pro-apoptotic gene promoter occupancy and target gene expression. In contrast, pre-silencing of Ash2L abrogated P53's ability to induce the expression of these transcriptional targets, without affecting P53 or RNAP II recruitment. However, Ash2L pre-silencing, under the same conditions, resulted in reduced RNAP II ser5-CTD phosphorylation on these same pro-apoptotic target promoters, which correlated with reduced promoter occupancy of TFIIB as well as TFIIF (RAP74). Based on these findings, we propose that Ash2L acts in concert with P53 promoter occupancy to activate RNAP II by aiding formation of a stable transcription pre-initiation complex required for its activation.
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Mungamuri
authors.affiliation: University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J J
authors.identifier: 0000000322349097
authors.initials: JJ
authors.lastname: Manfredi
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Gu
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Aaronson
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008780:Methyltransferases / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism*; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000096:biosynthesis; D035581:Transcription Factor TFIIB / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019473:Transcription Factors, TFII / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C485622:ASH2L protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D035581:Transcription Factor TFIIB; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D016159:Tumor Suppressor Protein p53; C502547:WDR5 protein, human; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II; C056604:transcription factor TFIIF