Seminar
Title：DNA Dependent Protein Kinase in DNA Damage Response, Stem Cell Maintenance, and Genomic Stability.
Reporter: Benjamin P.C. Chen
Assistant Professor
University of Texas Southwestern Medical Center
Department of Radiation Oncology, Molecular Radiation Biology Division
Host: Caixia Guo
Time：10:00-11:30 AM May 13, 2010
Location：Conference room 202, Beijing Institute of Genomics，CAS
Abstract: Proteins in the classical non homologous end joining (NHEJ) pathway are essential for radiation resistance and lymphocyte-specific V(D)J recombination. Defects in NHEJ also promote aging by impairing the function of hematopoietic stem cells (HSCs), but they do not significantly impact on the establishment long-term HSC reserves. For example, in mice defective in Ku80 DNA-binding subunit of DNA dependent protein kinase (DNA-PK), HSCs are maintained with regular number in young mice but reduced in aged mice. Here we show that in contrast to mice with null mutation of catalytic subunit of DNA-PK (DNA-PKcs-/-), DNA-PKcs knockin (DNA-PKcs3A/3A) mice with three alanine substitutions at the mouse thr2605 cluster of phosphorylation sites die due to congenital bone marrow failure within four weeks of birth. Premature death is caused by excessive DNA damage and activation of p53 dependent apoptosis in HSCs during fetal development. Surprisingly, our analysis reveals that DNA-PKcs3A/3A cells are hypersensitive to DNA cross-linking agent. Furthermore, the recruitments of the Fanconi anemia protein FANCD2 and homologous recombination (HR) protein RAD51 into DNA damage foci are attenuated in DNA-PKcs3A/3A cells. We conclude that phosphorylation of the NHEJ protein DNA-PKcs has impact beyond the NHEJ; it could regulate HR and possibly Fanconi anemia pathway, which in turn is essential for the establishment of HSCs.
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