LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
[146]. Brca1 is phosphorylated by the ATM protein [144]. ATM, which is mutated in the
radiationsensitive disorder ataxia-telangiectasia, is a candidate primary sensor of certain
types of DNA damage, particularly DSBs induced by ionizing radiation. Brca1 in
therefore a target for a key protein which signals the response to ionizing radiation.
Brca2–/– cells are also sensitive to DNA-damaging agents, although, curiously, display a
much more pronounced sensitivity to UV than to g-radiation. In addition, the massive
sensitization to mitomycin C which accompanies loss of Xrcc2 or Xrcc3 is not seen in the
Brca2–/– cells [146]. The likely involvement of Brca1 in HR, which is suggested by its
association with mRad51, is supported by the observation that there is relatively more
DSB repair by non-homologous pathways in Brca1–/– cells [123]. This is unlikely to be
the full story, however, because Brca1 also displays a DNA-damage-dependent
association with the hRad50/Mre11/Nbs1 complex [147]. This important tumor
suppressor therefore appears to participate in the two pathways of DSB repair.
Brca1 is also implicated in the removal of oxidized DNA bases from DNA. Damage is
selectively removed from the transcribed DNA strand by a process known as
transcription-coupled repair (TCR). Brca1-null cells are deficient in the TCR of DNA
thymine glycol produced by ionizing radiation or hydrogen peroxide but perform TCR of
UV induced DNA damage normally [143, 148]. It is unclear whether Brca1 participates
directly in TCR or indirectly via a signaling role. The involvement of Brca1 suggests that
the TCR of oxidized bases may represent a form of recombinational repair.
Cellular signaling functions and DSB repair
Many of the participants in DSB repair — including hMRE11, hRad50, DNA-PK, Ku
and Xrcc4 — are phosphoproteins. Brca1 and Brca2 are both phosphorylated in a cell-
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