LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 1 INTRODUCTION predominant pathway of DSB repair in yeast whereas mammalian cells presented with similar substrates use non-homologous or illegitimate pathways. This still seems to be the consensus although there is mounting evidence that DSB repair via homologous recombination in mammalian cells is more significant than was previously thought [122, 123]. In addition, there are indications that some proteins may participate in more than one of the three repair pathways. Fig. 1.3B Pathways of DSB repair. The termini of a DNA DSB introduced by ionising radiation or other means are bound either by the Ku heterodimer/DNA-PKcs complex or by hRad52. In the NHEJ rejoining pathway, repair is completed by DNA ligase IV and XRCC4. DNA strand invasion of the intact sister chromatid, facilitated by hRad51, initiates repair by homologous recombination. Resection and annealing of short regions of complementary sequence initiates repair by the SSA pathway in which ligation is preceded by the trimming of non-complementary single-stranded DNA tails. 53
CHAPTER 1 INTRODUCTION Non-homologous end rejoining Non-homologous end rejoining (NHEJ) has been considered the major pathway of DSB repair in mammalian cells (Fig. 1.3B). Repair is achieved without the need for extensive homology between the DNA ends to be joined. NHEJ processes the site-specific DSBs introduced during V(D)J (variable [division] joining) recombination and its importance is emphasised by the severe combined immune deficiency (SCID) and ionizing radiation sensitivity of mice with NHEJ defects. NHEJ involves a DNA end-binding heterodimer of the Ku70 and Ku80 proteins which activates the catalytic subunit (DNA-PKcs) of DNA-dependent protein kinase (DNA-PK) by stabilizing its interaction with DNA ends. This facilitates rejoining by a DNA ligase IV/Xrcc4 (X-ray cross-complementing 4) heterodimer [15]. The presence of constitutively high steady-state levels of DNA-PK is consistent with a role as a primary DNA damage recognition factor. The family of kinases to which DNA-PKcs belongs contains the important ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia Rad3-related) signalling proteins. All three proteins are serine/ threonine protein kinases which have some sequence similarity to phosphatidylinositol kinases. DNA-PK can phosphorylate p53 but the p53 response is apparently intact in DNA-PK-defective mouse cells which express wild-type p53 [124]. These rules out DNA-PK as an essential requirement for activation of the p53 DNA damage response. Other plausible targets for DNA-PK include the single stranded binding protein RPA (replication protein A), the DNA ligase IV cofactor Xrcc4, Ku, and DNA-PKcs itself. It is noteworthy that, although the stimulation of DNA ligase IV activity by phosphorylated and unphosphorylated forms of Xrcc4 is similar, phosphorylation of Xrcc4 may prevent its direct association with DNA [125]. This could 54
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RADIATION INDUCED SIGNALING IN MAMM
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DECLARATION I, hereby declare that
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CONTENTS Page No. SYNOPSIS………
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2.11 Measurement of NO production
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PREAMBLE SYNOPSIS Ionising radiatio
Page 12 and 13: SYNOPSIS Aims and Objectives: To St
Page 14 and 15: SYNOPSIS 2.6 Immunofluorescence sta
Page 16 and 17: SYNOPSIS ATM gene expression, which
Page 18 and 19: SYNOPSIS Percentage Survival 100 80
Page 20 and 21: SYNOPSIS Ratio of Rad52 to Actin Ra
Page 22 and 23: Relative Phosphorylation 45 40 35 3
Page 24 and 25: SYNOPSIS Fig. 3.3A Clonogenic Cell
Page 26 and 27: SYNOPSIS (A) Av No. of phospho BRCA
Page 28 and 29: SYNOPSIS Percentage Survival 120 10
Page 30 and 31: SYNOPSIS Fig.3.4B. Existance of cro
Page 32 and 33: SYNOPSIS Fig. 3.4EDNA damage in EL-
Page 34 and 35: SYNOPSIS subsequent cytotoxicity ca
Page 36 and 37: SYNOPSIS [4] Hall, E. J. Radiobiolo
Page 38 and 39: CHAPTER 1 INTRODUCTION INTRODUCTION
Page 40 and 41: CHAPTER 1 INTRODUCTION 15.8% 9.56%
Page 42 and 43: CHAPTER 1 INTRODUCTION far apart an
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Page 46 and 47: CHAPTER 1 INTRODUCTION 1.3 DNA dama
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Page 54 and 55: CHAPTER 1 INTRODUCTION occurs at DS
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Page 58 and 59: CHAPTER 1 INTRODUCTION damage must
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Page 70 and 71: CHAPTER 1 INTRODUCTION 1.4 Overview
Page 72 and 73: CHAPTER 1 INTRODUCTION 1.4.1 Radiat
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Page 76 and 77: CHAPTER 1 INTRODUCTION p90S6 kinase
Page 78 and 79: CHAPTER 1 INTRODUCTION CD4 (formerl
Page 80 and 81: CHAPTER 1 INTRODUCTION unrepaired d
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Page 84 and 85: CHAPTER 1 INTRODUCTION 1.6 Radiatio
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Page 88 and 89: CHAPTER 2 MATERIALS AND METHODS MAT
Page 90 and 91: CHAPTER 2 MATERIALS AND METHODS 2.2
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Page 96 and 97: CHAPTER 2 MATERIALS AND METHODS PBS
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Page 100 and 101: CHAPTER 2 MATERIALS AND METHODS 2.1
Page 102 and 103: CHAPTER 3 RESULTS RESULTS 93
Page 104 and 105: CHAPTER 3 RESULTS fractionated regi
Page 106 and 107: CHAPTER 3 RESULTS On comparison of
Page 108 and 109: CHAPTER 3 RESULTS Table 3.1.2A List
Page 110 and 111: CHAPTER 3 RESULTS 80 NM_002185 IL7R
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CHAPTER 3 RESULTS SAA2 149 AU134977
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CHAPTER 3 RESULTS 221 LOC643167 RNA
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CHAPTER 3 RESULTS 299 BF244402 FBXO
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CHAPTER 3 RESULTS CDK4) 57 AU152107
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CHAPTER 3 RESULTS 134 AL045793 METT
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CHAPTER 3 RESULTS 58 AF237813 ABAT
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CHAPTER 3 RESULTS 127 AI809749 ORMD
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CHAPTER 3 RESULTS 31 BE615699 UNC84
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CHAPTER 3 RESULTS 47 AF026303 SULT1
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CHAPTER 3 RESULTS 117 BF062193 CYor
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CHAPTER 3 RESULTS 187 AL036662 ---
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CHAPTER 3 RESULTS 52 AV686514 EMP2
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CHAPTER 3 RESULTS exposed to 10 Gy
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CHAPTER 3 RESULTS Fig.3.1.4 Gene ex
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CHAPTER 3 RESULTS Fig. 3.1.6 Radiat
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CHAPTER 3 RESULTS Fig. 3.1.7 Transl
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CHAPTER 3 RESULTS 3.1.9 Stabilizati
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CHAPTER 3 RESULTS 23±1.5% (Fig. 3.
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CHAPTER 3 RESULTS whereas only the
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CHAPTER 3 RESULTS with equal doses
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CHAPTER 3 RESULTS Fig.3.3.1.2 Forma
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CHAPTER 3 RESULTS Fig.3.3.1.3 Phosp
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CHAPTER 3 RESULTS (7.5±0.64) (Fig.
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CHAPTER 3 RESULTS Fig.3.3.1.7b Phos
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CHAPTER 3 RESULTS 3.3.2 Oxygen beam
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CHAPTER 3 RESULTS in all the cells.
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CHAPTER 3 RESULTS 3.3.2.3 Radiation
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CHAPTER 3 RESULTS Fig.3.3.2.7 Apopt
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CHAPTER 3 RESULTS PMA stimulated U9
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CHAPTER 3 RESULTS Fig.3.4.2. Exista
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CHAPTER 3 RESULTS up-regulation of
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CHAPTER 3 RESULTS Fig.3.4.3.2 NO pr
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CHAPTER 3 RESULTS 3.4.3.4 Apoptotic
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CHAPTER 3 RESULTS 3.4.4 Bystander e
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CHAPTER 3 RESULTS Fig.3.4.4b DNA da
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CHAPTER 3 RESULTS Fig.3.4.5a Gene e
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CHAPTER 4 DISCUSSION DISCUSSION 185
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CHAPTER 4 DISCUSSION directly expos
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CHAPTER 4 DISCUSSION dose is delive
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CHAPTER 4 DISCUSSION A clear cause
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CHAPTER 4 DISCUSSION 4.2 Proton bea
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CHAPTER 4 DISCUSSION Although the e
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CHAPTER 4 DISCUSSION Similar number
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CHAPTER 4 DISCUSSION the mechanism
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CHAPTER 4 DISCUSSION Thus unlike th
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CHAPTER 4 DISCUSSION different from
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CHAPTER 4 DISCUSSION upregulates ma
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CHAPTER 4 DISCUSSION Numerous studi
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CHAPTER 4 DISCUSSION inhibition of
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CHAPTER 4 DISCUSSION The survival o
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CHAPTER 5 REFERENCES [1] Khan, F. T
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CHAPTER 5 REFERENCES [19] Woo, R. A
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CHAPTER 5 REFERENCES [35] Nghiem, P
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CHAPTER 5 REFERENCES [52] McKay, B.
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CHAPTER 5 REFERENCES [69] Cary, R.
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CHAPTER 5 REFERENCES [84] Uziel, T.
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CHAPTER 5 REFERENCES [98] Liu, Y.;
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CHAPTER 5 REFERENCES [111] Fei, P.;
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CHAPTER 5 REFERENCES [127] Frank, K
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CHAPTER 5 REFERENCES [141] Pierce,
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CHAPTER 5 REFERENCES [156] Roots, R
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CHAPTER 5 REFERENCES [171] Xia, Z.;
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CHAPTER 5 REFERENCES (MAP) kinase c
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CHAPTER 5 REFERENCES phosphorylatio
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CHAPTER 5 REFERENCES [211] Anderson
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CHAPTER 5 REFERENCES [229] Konca, K
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CHAPTER 5 REFERENCES [245] Kastan,
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CHAPTER 5 REFERENCES [261] Miralbel
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CHAPTER 5 REFERENCES [278] Weizman,
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CHAPTER 5 REFERENCES [294] Zhou, H.
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PUBLICATIONS AND PRESENTATIONS Publ
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Mutation Research 729 (2012) 61-72
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S. Ghosh, M. Krishna / Mutation Res
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