LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
absence of overt defects in immune function. Radiation sensitivity and a modest defect in
DSB repair, but no significant impairment in V(D)J recombination, are associated with a
mutated DNA ligase IV in cells from a radiation-sensitive leukaemia patient [130]. The
absence of a detectable effect on V(D)J recombination indicates that an alternative DNArejoining
activity might partially substitute for defective Xrcc4/DNA ligase IV in these
cells. The occurrence of a DNA ligase IV defect in a leukaemia patient suggests that
reduced NHEJ might be a factor in the incidence of this disease.
Homologous recombination
S. cerevisiae has provided a useful model for homology directed recombination (HR)
processes. HR is performed by the RAD52 epistasis group of proteins which includes the
products of RAD50–55, RAD57, and RAD59, MRE11 and XRS2 [131]. Although
mammalian cells are considered to rely less on HR, they do perform mitotic
recombination and preferentially repair DSBs by HR in late S and G2 phases of the cell
cycle when an undamaged sister chromatid is available. Indeed, the DSB repair defect of
murine scid (severe combined immunodeficiency) cells is only apparent in G1/early S
phases [132]. The mammalian Rad51 protein is a homolog of the Escherichia coli RecA
protein and is involved in both meiotic and mitotic recombination. The S. cerevisiae and
human Rad51 proteins catalyse strand exchange in a reaction which is stimulated by
Rad52 and RPA [133, 134]. Human Rad52 has a DNA double-strand end binding activity
like Ku [135] and it probably co-operates with hRad51 in DSB repair but this is unlikely
to be the only important function of Rad51. Targeted inactivation of mRad51 results in
early embryonic lethality [136] whereas Rad52–/– mice are viable and fertile [137].
Rad52–/– murine stem cells, although deficient in recombination, are not detectably
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