LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 1 INTRODUCTION are unable to resolve the blockage of replication. Taken together, the replication machinery could be considered as an effective scanning apparatus that when blocked by DNA damage will recruit ATR kinase to sites of RPA-coated single-stranded DNA. This recruitment will then induce phosphorylation of numerous ATR substrates leading to the activation of S-phase and G2 cell cycle checkpoints and induction of DNA repair and/or apoptosis. 1.3.1.3 ATM: a DNA damage sensor for DNA homologous recombination repair and cell cycle arrest Ataxia-telangiectasia (A-T) is a rare human disease characterized by cerebellar degeneration, immune system defects and cancer predisposition [29, 56, 57]. The disease has been the subject of intense scientific scrutiny, particularly since the identification in 1995 of the gene mutated in A-T, ATM [58, 59]. The ataxia-telangiectasia mutated protein (ATM) has emerged as a central player in the cellular response to ionizing radiation (IR), in which it plays a critical role in the activation of cell cycle checkpoints that lead to DNA damage-induced arrest at G1/S, S, and G2/M. ATM is a member of the phosphatidylinositol 3-kinaselike family of serine/threonine protein kinases (PIKKs). Other members of this protein family include ATM- and Rad3-related (ATR), DNAdependent protein kinase catalytic subunit (DNA-PKcs), mammalian target of rapamycin (mTOR), and ATX/hSMG-1 [29, 60]. The PIKKs represent a subclass of “atypical” protein kinases within the overall eukaryotic protein kinase family [61]. ATM, like other members of this protein kinase family, phosphorylates its substrates on serine or threonine that is followed by glutamine, i.e. an SQ or TQ motif [62, 63]. ATM shares several features with other members of the PIKK family, including a FAT domain 41
CHAPTER 1 INTRODUCTION (named due to amino acid conservation between the PIKK family members FRAP, ATR, and TRRAP), a phosphoinositide 3,4-kinase (PI3K) domain and a FAT carboxy-terminal (FAT-C) domain [64]. One function of the FAT domain may be to interact with the kinase domain to stabilize the carboxy-terminal region of the protein [65]. Bioinformatics analysis indicates that the amino-terminal portions of ATM, ATR, mTOR and, likely, DNA-PKcs are composed of multiple huntingtin, elongation factor 3, A subunit of protein phosphatase 2A and TOR1 (HEAT) repeats [66]. Each HEAT repeat is composed of two interacting, anti-parallel alpha helices linked by a flexible loop. The amino-terminal regions of the PIKK proteins, therefore, are predicted to consist of multiple, interacting HEAT repeats that form a massive, superhelical scaffolding matrix [66]. While the function of the HEAT repeat domain remains unknown, it is speculated that it could provide a surface for interactions with other proteins. The first indications of the overall shape and dimensions of the ATM protein have recently emerged. Single particle electron microscopic analysis reveals that ATM has a large “head” domain of approximately 115Å by 75–140 Å, as well as a long “arm” structure that protrudes from the head region [67]. The overall shape of ATM is, thus, similar to that of the related protein, DNA-PKcs, at similar resolution [68]. Both proteins have the ability to interact with ends of doublestranded (ds) DNA[69-72], and this interaction may be facilitated by a conformational change that causes the arm region to wrap around the DNA [67]. From the low-resolution (30 Å) structure of ATM, it is speculated that the HEAT domain corresponds to the head structure and the carboxy-terminal kinase domain to the arm. However, elucidation of the precise molecular architecture of ATM will require a higher resolution structure. 42
Page 1: RADIATION INDUCED SIGNALING IN MAMM
Page 4 and 5: DECLARATION I, hereby declare that
Page 6 and 7: CONTENTS Page No. SYNOPSIS………
Page 8 and 9: 2.11 Measurement of NO production
Page 10 and 11: 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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CHAPTER 2 MATERIALS AND METHODS 2.1
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CHAPTER 3 RESULTS RESULTS 93
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CHAPTER 3 RESULTS fractionated regi
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CHAPTER 3 RESULTS On comparison of
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CHAPTER 3 RESULTS Table 3.1.2A List
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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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