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DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.

Publication ,  Journal Article
Nelson, WG; Kastan, MB
Published in: Mol Cell Biol
March 1994

The tumor suppressor protein p53 serves as a critical regulator of a G1 cell cycle checkpoint and of apoptosis following exposure of cells to DNA-damaging agents. The mechanism by which DNA-damaging agents elevate p53 protein levels to trigger G1/S arrest or cell death remains to be elucidated. In fact, whether damage to the DNA template itself participates in transducing the signal leading to p53 induction has not yet been demonstrated. We exposed human cell lines containing wild-type p53 alleles to several different DNA-damaging agents and found that agents which rapidly induce DNA strand breaks, such as ionizing radiation, bleomycin, and DNA topoisomerase-targeted drugs, rapidly triggered p53 protein elevations. In addition, we determined that camptothecin-stimulated trapping of topoisomerase I-DNA complexes was not sufficient to elevate p53 protein levels; rather, replication-associated DNA strand breaks were required. Furthermore, treatment of cells with the antimetabolite N(phosphonoacetyl)-L-aspartate (PALA) did not cause rapid p53 protein increases but resulted in delayed increases in p53 protein levels temporally correlated with the appearance of DNA strand breaks. Finally, we concluded that DNA strand breaks were sufficient for initiating p53-dependent signal transduction after finding that introduction of nucleases into cells by electroporation stimulated rapid p53 protein elevations. While DNA strand breaks appeared to be capable of triggering p53 induction, DNA lesions other than strand breaks did not. Exposure of normal cells and excision repair-deficient xeroderma pigmentosum cells to low doses of UV light, under conditions in which thymine dimers appear but DNA replication-associated strand breaks were prevented, resulted in p53 induction attributable to DNA strand breaks associated with excision repair. Our data indicate that DNA strand breaks are sufficient and probably necessary for p53 induction in cells with wild-type p53 alleles exposed to DNA-damaging agents.

Duke Scholars

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

March 1994

Volume

14

Issue

3

Start / End Page

1815 / 1823

Location

United States

Related Subject Headings

  • Ultraviolet Rays
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Topoisomerase I Inhibitors
  • In Vitro Techniques
  • Humans
  • Developmental Biology
  • DNA Repair
  • DNA Damage
  • DNA
 

Citation

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Nelson, W. G., & Kastan, M. B. (1994). DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol, 14(3), 1815–1823. https://doi.org/10.1128/mcb.14.3.1815-1823.1994
Nelson, W. G., and M. B. Kastan. “DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.Mol Cell Biol 14, no. 3 (March 1994): 1815–23. https://doi.org/10.1128/mcb.14.3.1815-1823.1994.
Nelson, W. G., and M. B. Kastan. “DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways.Mol Cell Biol, vol. 14, no. 3, Mar. 1994, pp. 1815–23. Pubmed, doi:10.1128/mcb.14.3.1815-1823.1994.

Published In

Mol Cell Biol

DOI

ISSN

0270-7306

Publication Date

March 1994

Volume

14

Issue

3

Start / End Page

1815 / 1823

Location

United States

Related Subject Headings

  • Ultraviolet Rays
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Topoisomerase I Inhibitors
  • In Vitro Techniques
  • Humans
  • Developmental Biology
  • DNA Repair
  • DNA Damage
  • DNA