title: p53-Independent apoptosis disrupts early organogenesis in embryos lacking both ataxia-telangiectasia mutated and Prkdc.
abstract: The ataxia-telangiectasia mutated (ATM) protein and the nonhomologous end-joining (NHEJ) pathway play crucial roles in sensing and repairing DNA double-strand breaks in postnatal cells. However, each pathway is dispensable for early embryogenesis. Loss of both ATM and Prkdc/Ku is synthetically lethal, but neither the developmental processes perturbed nor the mechanisms of lethality have been determined by previous reports. Here, we show that ATM and Prkdc collaborate to maintain genomic stability during gastrulation and early organogenesis, a period of rapid proliferation and hypersensitivity to DNA damage. At E7.5 to E8.5, ATM(-/-)Prkdcscid/scid embryos displayed normal proliferation indices but exhibited excessive apoptosis and elevated expression of Ser15-phosphorylated p53. Thus, this crucial regulatory residue of p53 can be phosphorylated in the absence of ATM or Prkdc. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that apoptosis is p53 independent in these in ATM(-/-)Prkdcscid/scid embryos. Because mice with combined disruptions of ATM and other NHEJ components (ligase IV, Artemis) are viable, our data suggest a novel NHEJ-independent function for Prkdc/Ku that is required to complete early embryogenesis in the absence of ATM.
authors: Program in Developmental Biology, Hospital for Sick Children Research Institute, Toronto Medical Discovery Tower Building (East Tower), Room 14-312, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
authors: Rebecca A
authors: RA
authors: Gladdy
authors: Lauryl M J
authors: LM
authors: Nutter
authors: Tilo
authors: T
authors: Kunath
authors: Jayne S
authors: JS
authors: Danska
authors: Cynthia J
authors: CJ
authors: Guidos