The controlling role of ATM in homologous recombinational repair of DNA damage

The human genetic disorder ataxia telangiectasia (A-T), caused by mutation in the ATM gene, is characterized by chromosomal instability, radiosensitiv ity and defective cell cycle checkpoint activation. DNA double-strand break s (dsbs) persist in A-T cells after irradiation, but the underlying defect is unclear. To investigate ATM's interactions with dsb repair pathways, we disrupted ATM along with other genes involved in the principal, complementa ry dsb repair pathways of homologous recombination (HR) or non-homologous e nd-joining (NHEJ) in chicken DT4O cells. ATM(-/-) cells show altered kineti cs of radiation-induced Rad51 and Rad54 focus formation. Ku70-deficient (NH EJ(-)) ATM(-/-) chicken DT40 cells show radiosensitivity and high radiation -induced chromosomal aberration frequencies, while Rad54-defective (HR-) AT M(-/-) cells show only slightly elevated aberration levels after irradiatio n, placing ATM and HR on the same pathway. These results reveal that ATM de fects impair HR-mediated dsb repair and may link cell cycle checkpoints to HR activation.