The aim of our
DNA repair studies is to elucidate excision repair and other
mechanisms of cellular recovery from DNA damage. Our goal is to help identify
human genes that determine the pathways for repair of, and recovery from, DNA
damage. Cloned genes provide the reagents for overproducing and purifying
repair proteins so that their specific biochemical functions can be determined.
Our major emphasis is on identifying new repair genes, purification and
analysis of repair proteins, understanding the role of these proteins in human
genetic diseases, and constructing mouse models for such diseases. We have
isolated DNA repair genes that are involved in human repair disorders,
particularly xeroderma pigmentosum (XP). We have identified mutations in the
ERCC2 gene of individuals from the diverse disorders XP, Cockayne's syndrome,
and trichothiodistrophy, which all result from abnormalities in this one gene.
Recent work using overexpressed, purified XRCC1 protein has shown an
interaction of XRCC1 with DNA ligase III in the rejoining step of base excision
repair, which acts on damage from ionizing radiation. Proteins that we plan to
derive from the recently cloned
ERCC4 and
XRCC3 genes are expected to provide
major insights into the mechanisms by which cells remove or respond to DNA
damage. To more fully understand the role of individual repair genes in the
whole animal, we are making transgenic mice (beginning with the
XRCC1 gene,
followed by the ERCC4 gene (likely XP group F). Moreover, a new gene has been
found (XRCC3) that will likely prove critical for understanding the mechanisms
of chromosome stability.
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