A G1 checkpoint mediated by the retinoblastoma protein that is dispensable in terminal differentiation but essential for senescence.
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.
Talluri
Srikanth
S
Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
Isaac
Christian E
CE
Ahmad
Mohammad
M
Henley
Shauna A
SA
Francis
Sarah M
SM
Martens
Alison L
AL
Bremner
Rod
R
Dick
Frederick A
FA
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
D050684:E2F Transcription Factors; D006570:Heterochromatin; D016160:Retinoblastoma Protein