James M. Larner, PhD
Radiation activation of ATM; S-phase damage-sensing checkpoints
Therapeutic irradiation is known to induce DNA damage, which is thought to activate multiple signaling pathways that regulate cell cycle checkpoints and gene transcription. ATM (mutated in ataxia telangiectasia) is thought to be a key sensor of DNA damage and transmits the damage signal to various downstream effort proteins including P53, Chk2, and BRCA1. They have recently identified the serine/threonine protein phosphatase 1 (PP1) as a downstream effector of IR-activated ATM. The functional consequences of IR-activated PP1 in response to DNA damage are poorly understood. However, data from their laboratory establish that IR activated PP1 regulates 1) HDAC1 activity and complex formation, and 2) centrosome separation through the Nek2 kinase. The long-term goal is to develop novel targets for chemo/radiation sensitizers by delineating the role of IR activated PP1 in checkpoint activation and gene transcription.