A G1 Checkpoint Mediated by the Retinoblastoma Protein That Is Dispensable in Terminal Differentiation but Essential for Senescence

Authors

Srikanth Talluri, University of Western Ontario
Christian E. Isaac, University of Western Ontario
Mohammad Ahmad, University of Toronto
Shauna A. Henley, University of Western Ontario
Sarah M. Francis, University of Western Ontario
Alison L. Martens, University of Western Ontario
Rod Bremner, University of Toronto
Frederick A. Dick, University of Western Ontario

Document Type

Article

Publication Date

2-2010

Journal

Molecular and Cellular Biology

Volume

30

Issue

4

First Page

948

Last Page

960

URL with Digital Object Identifier

http://dx.doi.org/10.1128/MCB.01168-09

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.