RB-dependent S-phase response to DNA damage

K. E. Knudsen, D. Booth, S. Naderi, Z. Sever-Chroneos, A. F. Fribourg, I. C. Hunton, J. R. Feramisco, J. Y J Wang, E. S. Knudsen

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185 Scopus citations

Abstract

The retinoblastoma tumor suppressor protein (RB) is a potent inhibitor of cell proliferation. Rb is expressed throughout the cell cycle, but its antiproliferative activity is neutralized by phosphorylation during the G1/S transition. Rb plays an essential role in the G1 arrest induced by a variety of growth inhibitory signals. In this report, RB is shown to also be required for an intra-S-phase response to DNA damage. Treatment with cisplatin, etoposide, or mitomycin C inhibited S-phase progression in Rb(+/+) but not in Rb(-/-) mouse embryo fibroblasts. Dephosphorylation of RB in S-phase cells temporally preceded the inhibition of DNA synthesis. This S-phase dephosphorylation of RB and subsequent inhibition of DNA replication was observed in p21(Cip1) deficient cells. The induction of the RB-dependent intra-S-phase arrest persisted for days and correlated with a protection against DNA damage-induced cell death. These results demonstrate that RB plays a protective role in response to genotoxic stress by inhibiting cell cycle progression in G1 and in S phase.

Original languageEnglish (US)
Pages (from-to)7751-7763
Number of pages13
JournalMolecular and cellular biology
Volume20
Issue number20
DOIs
StatePublished - Jan 1 2000

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Knudsen, K. E., Booth, D., Naderi, S., Sever-Chroneos, Z., Fribourg, A. F., Hunton, I. C., Feramisco, J. R., Wang, J. Y. J., & Knudsen, E. S. (2000). RB-dependent S-phase response to DNA damage. Molecular and cellular biology, 20(20), 7751-7763. https://doi.org/10.1128/MCB.20.20.7751-7763.2000