LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 4 DISCUSSION Similar number of γ-H2AX foci at 15 minutes after irradiation irrespective of the radiation quality indicated that initial events might not differ much with the radiation quality. Activation of other molecules including ATM, ATR, BRCA1, Chk1, Chk2 and Bax was therefore followed only at later time point of 4 hours. Moreover, since by this time most of the damage would be repaired, comparing the activation of these molecules at this time could highlight signaling differences with respect to clustered damage. ATM and ATR, the initial DNA damage sensors, are critical regulators of cell cycle checkpoints and repair. ATM has particularly been shown to respond to IR induced damage. Presence of few ATM foci in ~90% of the gamma irradiated cells 4 hours after irradiation indicates the repair of the damage in most cells. However, in carbon-irradiated cells, although the percentage of cells showing the pATM foci (55%) was less, the average number of foci/cell was more (Fig.3.3.1.3). Similar trend was also observed with ATR foci with respect to radiation quality (Fig.3.3.1.4). Higher percentage of gamma irradiated cells showing the ATM/ATR foci 4 hours after irradiation as compared to carbon irradiated cells indicates more homogenous nature of gamma radiation induced responses while presence of lesser average ATM/ATR foci per gamma irradiated cell as against carbon irradiation indicates efficient repair after gamma. This observation is in agreement with the previous studies where higher activation of repair molecules had been observed few hours after heavy ion irradiation as compared to low LET irradiation [214, 275] and has been attributed to unrepaired DNA that keeps the damage sensors in activated state. The formation of BRCA1 foci was unlike ATM/ATR and very interesting. BRCA1 exists in a complex containing ATM and other DSB repair proteins and both ATM and BRCA1 have been 197
CHAPTER 4 DISCUSSION regarded as primary regulators of HRR [251]. Presence of BRCA1 foci in ~55% (Fig.3.3.1.5) of the gamma irradiated cells is in agreement with the previous studies where BRCA1 foci have been found to be activated only in cells in S, G2/M phases of the cycle [275] and therefore is thought to play a role in HRR which can take the advantage of the other strand that may be intact. Unlike after gamma irradiation, presence of BRCA1 foci in all of the carbon irradiated cells was quite intriguing. Moreover, the downstream substrates, Chk1 (Fig.3.3.1.6A) and Chk2 (Fig.3.3.1.6C) also showed relatively higher activation in carbon irradiated cells as compared to gamma. Activation of all these repair components with high LET radiation at first indicates persistent and even more intense activation of repair pathways. However, presence of ATM foci in only half of carbon irradiated cells while BRCA1 foci in all cells suggest that BRCA1 is associated with different proteins and may not require activated ATM. The larger size of BRCA1 foci after Carbon irradiation also indicated that macromolecular complexes containing BRCA1 might be different after two types of radiation treatments. Number of Chk2 foci, another important regulator of HRR, also did not seem to parallel ATM foci. This, along with the fact that the survival of the cells is only 20% (Fig.3.3.1.1) and many apoptotic nuclei are present at 4 hours (Fig.3.3.1.8) indicates that these macromolecular complexes containing BRCA1 may be majorly involved in apoptotic responses after a complex damage to the DNA. Recent studies suggest multifunctional nature of BRCA1 in maintaining genome integrity. It has been shown to play an important role in apoptosis and cell cycle control and does so by associating in distinct protein complexes [276]. The cytoplasmic MAPK pathways, ERK and JNK, that feed into and are fed upon by DNA damage repair signaling also play an equally important role in deciding the fate of the irradiated cell. Reactive oxygen species generated after gamma irradiation have been thought to be one of 198
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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
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SYNOPSIS Aims and Objectives: To St
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SYNOPSIS 2.6 Immunofluorescence sta
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SYNOPSIS ATM gene expression, which
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SYNOPSIS Percentage Survival 100 80
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SYNOPSIS Ratio of Rad52 to Actin Ra
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Relative Phosphorylation 45 40 35 3
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SYNOPSIS Fig. 3.3A Clonogenic Cell
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SYNOPSIS (A) Av No. of phospho BRCA
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SYNOPSIS Percentage Survival 120 10
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SYNOPSIS Fig.3.4B. Existance of cro
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SYNOPSIS Fig. 3.4EDNA damage in EL-
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SYNOPSIS subsequent cytotoxicity ca
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SYNOPSIS [4] Hall, E. J. Radiobiolo
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CHAPTER 1 INTRODUCTION INTRODUCTION
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CHAPTER 1 INTRODUCTION 15.8% 9.56%
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CHAPTER 1 INTRODUCTION far apart an
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CHAPTER 1 INTRODUCTION and are more
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CHAPTER 1 INTRODUCTION 1.3 DNA dama
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CHAPTER 1 INTRODUCTION associates w
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CHAPTER 1 INTRODUCTION are unable t
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CHAPTER 1 INTRODUCTION Perhaps one
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CHAPTER 1 INTRODUCTION occurs at DS
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CHAPTER 1 INTRODUCTION related prot
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CHAPTER 1 INTRODUCTION damage must
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CHAPTER 1 INTRODUCTION At the prese
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CHAPTER 1 INTRODUCTION predominant
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CHAPTER 1 INTRODUCTION provide a me
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CHAPTER 1 INTRODUCTION hypersensiti
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CHAPTER 1 INTRODUCTION cycle-specif
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CHAPTER 1 INTRODUCTION 1.4 Overview
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CHAPTER 1 INTRODUCTION 1.4.1 Radiat
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CHAPTER 1 INTRODUCTION interaction
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CHAPTER 1 INTRODUCTION p90S6 kinase
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CHAPTER 1 INTRODUCTION CD4 (formerl
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CHAPTER 1 INTRODUCTION unrepaired d
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CHAPTER 1 INTRODUCTION well to the
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CHAPTER 1 INTRODUCTION 1.6 Radiatio
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CHAPTER 1 INTRODUCTION becomes pote
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CHAPTER 2 MATERIALS AND METHODS MAT
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CHAPTER 2 MATERIALS AND METHODS 2.2
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CHAPTER 2 MATERIALS AND METHODS res
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CHAPTER 2 MATERIALS AND METHODS Arr
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CHAPTER 2 MATERIALS AND METHODS PBS
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CHAPTER 2 MATERIALS AND METHODS the
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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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Page 170 and 171: CHAPTER 3 RESULTS 3.3.2.3 Radiation
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Page 190 and 191: CHAPTER 3 RESULTS Fig.3.4.4b DNA da
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Page 222 and 223: CHAPTER 5 REFERENCES [1] Khan, F. T
Page 224 and 225: CHAPTER 5 REFERENCES [19] Woo, R. A
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Page 230 and 231: CHAPTER 5 REFERENCES [69] Cary, R.
Page 232 and 233: CHAPTER 5 REFERENCES [84] Uziel, T.
Page 234 and 235: CHAPTER 5 REFERENCES [98] Liu, Y.;
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Page 238 and 239: CHAPTER 5 REFERENCES [127] Frank, K
Page 240 and 241: CHAPTER 5 REFERENCES [141] Pierce,
Page 242 and 243: CHAPTER 5 REFERENCES [156] Roots, R
Page 244 and 245: CHAPTER 5 REFERENCES [171] Xia, Z.;
Page 246 and 247: CHAPTER 5 REFERENCES (MAP) kinase c
Page 248 and 249: CHAPTER 5 REFERENCES phosphorylatio
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Page 252 and 253: CHAPTER 5 REFERENCES [229] Konca, K
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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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