Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation

ATM is a member of the large phosphatidylinositol-3 kinase family and plays an important role in cellular response to DNA damage. To further define th e physiological roles of ATM at the cellular level, me created an isogenic set of stable cell lines differing only in their ATM status from the chicke n B cell line DT40 by targeted integration. These stable DT40 cell lines, a s most of transformed chicken cell lines, do not express p53. However, ATM( -/-) DT40 cells displayed retarded cellular proliferation, defective G(2)/M checkpoint control and radio-resistant DNA synthesis. Furthermore, ATM(-/- ) DT40 cells were sensitive to ionizing radiation and showed highly elevate d frequencies of both spontaneous and radiation-induced chromosomal aberrat ions. In addition, a slight but significant reduction in targeted integrati on frequency was observed in,ATM(-/-) DT40 cells. These results suggest tha t ATM has multiple p53-independent functions in cell cycle checkpoint contr ol and in maintenance of chromosomal DNA. These ATM deficient DT40 clones t herefore provide a useful model system for analysing p53-independent ATM fu nctions.