Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 20, Pages 9207-9220Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.20.9207-9220.2004
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Funding
- NCI NIH HHS [CA96574, CA90270, R01 CA096574, R01 CA052461, CA52461, P50 CA090270] Funding Source: Medline
- NIEHS NIH HHS [P30 ES007784, ES07784] Funding Source: Medline
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Mutations in Artemis in both humans and mice result in severe combined immunodeficiency due to a defect in V(D)J recombination. In addition, Artemis mutants are radiosensitive and chromosomally unstable, which has been attributed to a defect in nonhomologous end joining (NHEJ). We show here, however, that Artemis-depleted cell extracts are not defective in NHEJ and that Artemis-deficient cells have normal repair kinetics of double-strand breaks after exposure to ionizing radiation (IR). Artemis is shown, however, to interact with known cell cycle checkpoint proteins and to be a phosphorylation target of the checkpoint kinase ATM or ATR after exposure of cells to IR or UV irradiation, respectively. Consistent with these findings, our results also show that Artemis is required for the maintenance of a normal DNA damage-induced G(2)/M cell cycle arrest. Artemis does not appear, however, to act either upstream or downstream of checkpoint kinase Chk1 or Chk2. These results define Artemis as having a checkpoint function and suggest that the radiosensitivity and chromosomal instability of Artemis-deficient cells may be due to defects in cell cycle responses after DNA damage.
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