HOMOLOGOUS RECOMBINATION IN MAMMALIAN CELLS

Recombination of DNA molecules is a fundamental biological process that
influences genetic diversity within a species, repair of DNA damage and
gene expression during development, eg. the "uncovering" of recessive
oncogenes in certain inherited forms of human cancer. Although
considerable progress has been made toward elucidating the mechanism of
extrachromosomal recombination events in cultured mammalian cells, less is
known about events that occur in the chromosome. A mechanistic
understanding of chromosomal recombination is intrinsically important and
impacts directly on strategies used for the genetic manipulation of the
mammalian genome via homologous recombination (gene targeting). To gain
additional insight into homologous chromosomal recombination we will: 1)
Determine what step in chromosomal recombination is inhibited by large
insertions of heterologous DNA; 2) Apply a direct genetic test to detect
and allow study of the repair of heteroduplex DNA intermediates during
spontaneous and double-strand break induced intermediates during
spontaneous and double-strand break induced intrachromosomal recombination
3) Test the repair, via intrachromosomal and interchromosomal
recombination, of double-stranded breaks in DNA produced in vivo; and 4)
Develop a system to study spontaneous and carcinogen-induced intragenic
recombination between homologous chromosomes.