title: Rap1 relocalization contributes to the chromatin-mediated gene expression profile and pace of cell senescence.
abstract: Cellular senescence is accompanied by dramatic changes in chromatin structure and gene expression. Using Saccharomyces cerevisiae mutants lacking telomerase (tlc1Δ) to model senescence, we found that with critical telomere shortening, the telomere-binding protein Rap1 (repressor activator protein 1) relocalizes to the upstream promoter regions of hundreds of new target genes. The set of new Rap1 targets at senescence (NRTS) is preferentially activated at senescence, and experimental manipulations of Rap1 levels indicate that it contributes directly to NRTS activation. A notable subset of NRTS includes the core histone-encoding genes; we found that Rap1 contributes to their repression and that histone protein levels decline at senescence. Rap1 and histones also display a target site-specific antagonism that leads to diminished nucleosome occupancy at the promoters of up-regulated NRTS. This antagonism apparently impacts the rate of senescence because underexpression of Rap1 or overexpression of the core histones delays senescence. Rap1 relocalization is not a simple consequence of lost telomere-binding sites, but rather depends on the Mec1 checkpoint kinase. Rap1 relocalization is thus a novel mechanism connecting DNA damage responses (DDRs) at telomeres to global changes in chromatin and gene expression while driving the pace of senescence.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Platt
authors.forename: Paul
authors.initials: P
authors.lastname: Ryvkin
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wanat
authors.forename: Greg
authors.initials: G
authors.lastname: Donahue
authors.forename: M Dan
authors.initials: MD
authors.lastname: Ricketts
authors.forename: Steven P
authors.initials: SP
authors.lastname: Barrett
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Waters
authors.forename: Shufei
authors.initials: S
authors.lastname: Song
authors.forename: Alejandro
authors.initials: A
authors.lastname: Chavez
authors.forename: Khaled Omar
authors.initials: KO
authors.lastname: Abdallah
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Master
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006657:Histones / Q000235:genetics; D050296:Microbial Viability; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D002843:Chromatin; D006657:Histones; C440829:RAP1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D014157:Transcription Factors
keywords: PI3-like kinase; Rap1; cellular senescence; chromatin; histones; telomere