LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
hypersensitive to the presence of DSBs. Animals which are null for a third member of the
RAD52 family, mRad54, are also viable and fertile but, in this case, their cells are
hypersensitive to DSB-inducing agents [138]. Unraveling the biochemical functions of
these mammalian RAD52 family members — and defining the essential functions of the
Rad51 and Rad54 proteins — is clearly a high priority. At present, it is clear that they are
not functionally identical to their yeast counterparts. Human Rad51 forms discrete foci in
the nuclei of cells exposed to ionising radiation (but not UV) or chemicals. In rodents,
DNA damage-induced mRad51 focus formation requires mRad54 [139]. As both
mRad51 and mRad54 null cells are sensitive to ionising radiation, the direct participation
of mRad54 and mRad51 in DSB repair is implied. Human cells are known to express two
other Rad51-related proteins — Xrcc2 and Xrcc3 — both of which interact with Rad51
and influence DSB repair by HR [140, 141]. Confusingly, although mRad54-null and
Xrcc3-deficient cells are both sensitive to ionising radiation, only the latter are crosssensitive
to UV light. An important recent development has been the realization that the
products of the human breast cancer susceptibility genes BRCA1 and BRCA2 are involved
in DNA repair. In fact, the carboxy-terminal region (BRCT domain) of these proteins
defines a common motif among DNA-repair proteins [142]. Loss of functional Brca1
results in sensitivity (albeit slight) to radiation and DNA-damaging chemicals [143, 144].
A fraction of hRad51 colocalises with Brca1 and Brca2 in mitotic cells. Following DNA
damage, the three proteins are relocated to structures which also contain PCNA
(proliferating cell nuclear antigen) and may represent sites of active repair [145]. Both
Brca2–/– and Brca1–/– mouse fibroblasts develop spontaneous chromosome aberrations
consistent with the participation of these proteins in the repair of spontaneous DSBs
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