title: The retinoblastoma protein and PML collaborate to organize heterochromatin and silence E2F-responsive genes during senescence.
abstract: Cellular senescence is characterized by silencing of genes involved in DNA replication and cell cycle progression. Stable repression is crucial for preventing inappropriate DNA synthesis and the maintenance of a prolonged senescent state. Many of these genes are targets for E2F transcription factors. The pRB pathway plays a major role in senescence by directly repressing E2Fs and also by regulating chromatin at the promoters of E2F target genes using its LXCXE cleft-dependent interactions. In this study, we sought to investigate the mechanisms by which pRB stably silences E2F target gene transcription during cellular senescence. We report that in mouse embryonic fibroblasts, endogenous promyelocytic leukemia protein (PML) associates with E2F target genes in a pRB LXCXE-dependent manner during HrasV12-induced senescence. Furthermore, using a PML-IV-induced senescence model, we show that the pRB LXCXE binding cleft is essential for PML association with gene promoters, silencing of E2F target genes, and stable cell cycle exit. Binding assays show that pRB can interact with PML specifically during senescence, suggesting that signaling events in senescence regulate assembly of PML and pRB to establish heterochromatin and create a permanent cell cycle arrest.
authors.affiliation: London Regional Cancer Program; Western University; London, Ontario, Canada; Department of Biochemistry; Western University; London, Ontario, Canada.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Talluri
authors.affiliation: London Regional Cancer Program; Western University; London, Ontario, Canada; Department of Biochemistry; Western University; London, Ontario, Canada; Children's Health Research Institute; Western University; London, Ontario, Canada.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D055503:Protein Multimerization; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; D006570:Heterochromatin; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: E2F; PML; cell cycle; heterochromatin; senescence; transcription