title: The retinoblastoma protein selectively represses E2F1 targets via a TAAC DNA element during cellular senescence.
abstract: The retinoblastoma (Rb) protein mediates heterochromatin formation at the promoters of E2 transcription factor 1 (E2F1) target genes, such as proliferating cell nuclear antigen and cyclin A2 (CCNA2), and represses these genes during cellular senescence. However, the selectivity of Rb recruitment is still not well understood. Here, we demonstrate that a senescence-associated gene is a direct target of E2F1 and is also repressed by heterochromatin in senescent cells. In contrast, ARF and p27(KIP1), which are also E2F1 targets, are not repressed by Rb and heterochromatin formation. By comparing the promoter sequences of these genes, we found a novel TAAC element that is present in the cellular senescence-inhibited gene, proliferating cell nuclear antigen, and CCNA2 promoters but absent from the ARF and p27(KIP1) promoters. This TAAC element associates with Rb and is required for Rb recruitment. We further determined that TAAC element-mediated Rb association requires the E2F1 binding site, but not E2F1 protein. These results provide a novel molecular mechanism for the different expression patterns of E2F1 targets and afford new mechanistic insight regarding the selectivity of Rb-mediated heterochromatin formation and gene repression during cellular senescence.
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Tianda
authors.initials: T
authors.lastname: Chen
authors.forename: Lixiang
authors.initials: L
authors.lastname: Xue
authors.forename: Jing
authors.initials: J
authors.lastname: Niu
authors.forename: Liwei
authors.initials: L
authors.lastname: Ma
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Cao
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhao
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Jiamu
authors.initials: J
authors.lastname: Wang
authors.forename: Tanjun
authors.initials: T
authors.lastname: Tong
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D056751:Cyclin A2 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: C503721:CCNA2 protein, human; D056751:Cyclin A2; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D006570:Heterochromatin; D011257:Pregnancy Proteins; D018809:Proliferating Cell Nuclear Antigen; C117409:RSL1D1 protein, human; D016160:Retinoblastoma Protein; D012269:Ribosomal Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D049410:Luciferases, Renilla; D020727:ADP-Ribosylation Factors