||The protection of genomic integrity is a major challenge for living cells which are
continuously exposed to endogenous and environmental DNA-damaging agents. To cope
with the deadly consequences of DNA lesions, cells are equipped with an efficient
defense mechanism termed the DNA damage response. Its function is to eliminate DNA
damage by DNA repair and to remove cells with incurred DNA damage by the activation
of programmed cell death. Since DNA is perhaps the major target of oxyradicals, and
neurons are particularly susceptible to oxidative stress because of the high rate
of oxidative metabolism in the brain, the DNA damage response is critically important
for neurons. The DNA damage response has been investigated mainly in proliferating
cells, in which the cell cycle machinery is integrated with the DNA damage signaling.
Given the postmitotic nature of neurons, the DNA damage response was not expected
to activate the cell cycle checkpoints. However, evidence is emerging that in neurodegenerative
diseases, dying neurons attempt to reenter the cell cycle which may play a role in
pathogenesis of neurodegenerative diseases. The purpose of this cell cycle reentry
is unknown. Given a high metabolic rate, continuous exposure to oxidative stress
and extensive gene transcription, the importance of the DNA damage response for maintaining
genomic stability in neurons cannot be overemphasized. Dr. Kruman's current work
focuses on DNA damage response of postmitotic neurons and a role for the cell cycle
machinery in DNA repair and DNA damage-initiated programmed cell death in postmitotic
neurons and the contribution of these processes to neurodegeneration.
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