Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 13, Pages 5063-5068Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0801235105
Keywords
cell cycle checkpoint; DNA repair; radiation sensitivity
Categories
Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NIA NIH HHS [K99 AG029726, P30 AG021342, 1 K99 AG029726-01, R01 AG025142] Funding Source: Medline
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The type IA topoisomerases have been implicated in the repair of dsDNA breaks by homologous recombination and in the resolution of stalled or damaged DNA replication forks; thus, these proteins play important roles in the maintenance of genomic stability. We studied the functions of one of the two mammalian type IA enzymes, Top3 beta, using murine embryonic fibroblasts (MEFs) derived from top3 beta(-/-) embryos. top3 beta(-/-) MEFs proliferated more slowly than TOP3 beta(+/+) control MEFs, demonstrated increased sensitivity to DNA-damaging agents such as ionizing and UV radiation, and had increased DNA double-strand breaks as manifested by increased gamma-H2-AX phosphorylation. However, incomplete enforcement of the G(1)-S cell cycle checkpoint was observed in top3 beta(-/-) MEFs. Notably, ataxia-telangiectasia, mutated (ATM)/ATM and Rad3-related (ATR)-dependent substrate phosphorylation after UV-B and ionizing radiation was impaired in top3 beta(-/-) versus TOP3 beta(+/+) control MEFs, and impaired up-regulation of total and Ser-18-phosphorylated p53 was observed in top3 beta(-/-) cells. Taken together, these results suggest an unanticipated role for Top3 beta beyond DNA repair in the activation of cellular responses to DNA damage.
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