Genetic approaches have provided evidence that DNA end-joining problems ser
ve an essential role in neuronal survival during development of mammalian e
mbryos. In the present study, we tested whether the DNA repair enzyme, DNA
dependent protein kinase, plays an important role in the survival of cerebr
al cortical neurons in mice. DNA-PK is comprised of a DNA-binding subunit c
alled Ku and a catalytic subunit called DNA-PKcs. In mice with the scid mut
ation, DNA-PKcs is truncated near the kinase domain, which causes loss of k
inase activity. We compared the spatial and temporal aspects of neuronal ce
ll death in scid versus isogenic wildtype embryos and found a significant i
ncrease in dying cells in scid mice, as assessed by nuclear changes, DNA fr
agmentation and caspase-3 activity. Additional biochemical and immunocytoch
emical studies indicated that of several DNA repair enzymes investigated, o
nly PARP was increased in scid mice, possibly in response to elevated DNA s
trand breaks.