This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Offer, H. Articles by Rotter, V. Search for Related Content PubMed PubMed Citation Articles by Offer, H. Articles by Rotter, V.

p53 Modulates Base Excision Repair Activity in a Cell Cycle-specific Manner after Genotoxic Stress¹

Departments of Molecular Cell Biology [H. O., I. Z., A. F., M. M., N. G., V. R.] and Biological Chemistry [G. B., M. R.], Weizmann Institute of Science, Rehovot 76100, Israel

To elucidate the nature of the cross-talk between the p53 protein and the DNA repair machinery, we have investigated the relationship between the two throughout the cell cycle. Base excision repair (BER) was analyzed in cell cycle phase-enriched populations of lymphoid cells expressing wild-type p53. Our study yielded the following novel findings: (a) BER exhibited two distinct peaks of activity, one associated with the G₀-G₁ checkpoint and the second with the G₂-M checkpoint; (b) although the overall BER activity was reduced after exposure of cells to 400R, there was an augmentation of the G₀-G₁-associated BER activity and a reduction in the G₂-M-associated BER activity; and (c) modulations in these patterns of BER after genotoxic stress were found to be p53 regulated. p53 protein levels induced after -irradiation were distributed evenly in the various cell cycle populations (analyzed by the PAb-248 anti-p53 monoclonal antibody). However, both the dephosphorylation of serine 376 of p53 (contained in the PAb-421 epitope) and the specific DNA binding activity, as well as apoptosis, were enhanced toward the G₂-M populations. Furthermore, inactivation of wild-type p53, mediated by mutant p53 expression, abolished the alterations in the BER pattern and showed no induction of a G₂-M-associated apoptosis after -irradiation. These results suggest that after genotoxic stress, stabilized p53 enhances the G₀-G₁-associated BER activity, whereas it predominantly reduces BER activity at the G₂-M-enriched populations and instead induces apoptosis. After genotoxic stress, p53 functions as a modulator that determines the pattern of BER activity and apoptosis in a cell cycle-specific manner.

This article has been cited by other articles:

				S. M. K. Pulukuri, J. A. Knost, N. Estes, and J. S. Rao Small Interfering RNA-Directed Knockdown of Uracil DNA Glycosylase Induces Apoptosis and Sensitizes Human Prostate Cancer Cells to Genotoxic Stress Mol. Cancer Res., August 1, 2009; 7(8): 1285 - 1293. [Abstract] [Full Text] [PDF]

				S. N. Kassam and A. J. Rainbow UV-inducible base excision repair of oxidative damaged DNA in human cells Mutagenesis, January 1, 2009; 24(1): 75 - 83. [Abstract] [Full Text] [PDF]

				D. Menendez, A. Inga, and M. A. Resnick The Biological Impact of the Human Master Regulator p53 Can Be Altered by Mutations That Change the Spectrum and Expression of Its Target Genes. Mol. Cell. Biol., March 1, 2006; 26(6): 2297 - 2308. [Abstract] [Full Text] [PDF]

				X. Wu, J. A. Roth, H. Zhao, S. Luo, Y.-L. Zheng, S. Chiang, and M. R. Spitz Cell Cycle Checkpoints, DNA Damage/Repair, and Lung Cancer Risk Cancer Res., January 1, 2005; 65(1): 349 - 357. [Abstract] [Full Text] [PDF]

				N. Sugo, N. Niimi, Y. Aratani, K. Takiguchi-Hayashi, and H. Koyama p53 Deficiency Rescues Neuronal Apoptosis but Not Differentiation in DNA Polymerase {beta}-Deficient Mice Mol. Cell. Biol., November 1, 2004; 24(21): 9470 - 9477. [Abstract] [Full Text] [PDF]

				I. Zurer, L. J. Hofseth, Y. Cohen, M. Xu-Welliver, S. P. Hussain, C. C. Harris, and V. Rotter The role of p53 in base excision repair following genotoxic stress Carcinogenesis, January 1, 2004; 25(1): 11 - 19. [Abstract] [Full Text] [PDF]

				S. L. Scott, J. D. Earle, and P. H. Gumerlock Functional p53 Increases Prostate Cancer Cell Survival After Exposure to Fractionated Doses of Ionizing Radiation Cancer Res., November 1, 2003; 63(21): 7190 - 7196. [Abstract] [Full Text] [PDF]

				N. K. Sah, A. Munshi, T. Nishikawa, T. Mukhopadhyay, J. A. Roth, and R. E. Meyn Adenovirus-mediated wild-type p53 radiosensitizes human tumor cells by suppressing DNA repair capacity Mol. Cancer Ther., November 1, 2003; 2(11): 1223 - 1231. [Abstract] [Full Text] [PDF]

				D. R. Lloyd and P. C. Hanawalt p53 Controls Global Nucleotide Excision Repair of Low Levels of Structurally Diverse Benzo(g)chrysene-DNA Adducts in Human Fibroblasts Cancer Res., September 15, 2002; 62(18): 5288 - 5294. [Abstract] [Full Text] [PDF]

				L. Liu, Y. Nakatsuru, and S. L. Gerson Base Excision Repair as a Therapeutic Target in Colon Cancer Clin. Cancer Res., September 1, 2002; 8(9): 2985 - 2991. [Abstract] [Full Text] [PDF]

				H. Offer, N. Erez, I. Zurer, X. Tang, M. Milyavsky, N. Goldfinger, and V. Rotter The onset of p53-dependent DNA repair or apoptosis is determined by the level of accumulated damaged DNA Carcinogenesis, June 1, 2002; 23(6): 1025 - 1032. [Abstract] [Full Text] [PDF]

				M. L. Smith and Y. R. Seo p53 regulation of DNA excision repair pathways Mutagenesis, March 1, 2002; 17(2): 149 - 156. [Abstract] [Full Text] [PDF]

				A. M. d. M. C. Gontijo, F. N. Elias, D. M. F. Salvadori, M. L. C. S. de Oliveira, L. A. Correa, J. Goldberg, J. C. d. S. Trindade, and J. L. V. de Camargo Single-Cell Gel (Comet) Assay Detects Primary DNA Damage in Nonneoplastic Urothelial Cells of Smokers and Ex-smokers Cancer Epidemiol. Biomarkers Prev., September 1, 2001; 10(9): 987 - 993. [Abstract] [Full Text] [PDF]

				G. Frosina Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes Carcinogenesis, September 1, 2001; 22(9): 1335 - 1341. [Abstract] [Full Text] [PDF]