title: A G1 checkpoint mediated by the retinoblastoma protein that is dispensable in terminal differentiation but essential for senescence.
abstract: Terminally differentiated cell types are needed to live and function in a postmitotic state for a lifetime. Cellular senescence is another type of permanent arrest that blocks the proliferation of cells in response to genotoxic stress. Here we show that the retinoblastoma protein (pRB) uses a mechanism to block DNA replication in senescence that is distinct from its role in permanent cell cycle exit associated with terminal differentiation. Our work demonstrates that a subtle mutation in pRB that cripples its ability to interact with chromatin regulators impairs heterochromatinization and repression of E2F-responsive promoters during senescence. In contrast, terminally differentiated nerve and muscle cells bearing the same mutation fully exit the cell cycle and block E2F-responsive gene expression by a different mechanism. Remarkably, this reveals that pRB recruits chromatin regulators primarily to engage a stress-responsive G(1) arrest program.
authors.affiliation: Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Talluri
authors.forename: Christian E
authors.initials: CE
authors.lastname: Isaac
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ahmad
authors.forename: Shauna A
authors.initials: SA
authors.lastname: Henley
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Francis
authors.forename: Alison L
authors.initials: AL
authors.lastname: Martens
authors.forename: Rod
authors.initials: R
authors.lastname: Bremner
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D016922:Cellular Senescence; D004261:DNA Replication; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050684:E2F Transcription Factors; D006570:Heterochromatin; D016160:Retinoblastoma Protein