Predictive Genomics: A Post-genomic Integrated Approach to Analyse Biological Signatures of Radiation Exposure

The ultimate objective of radiation research is to link human diseases with the altered gene expression that underlie them and the exposure type and level that caused them. However, this has remained a daunting task for radiation biologists to indent genomic signatures of radiation exposures. Transcriptomic analysis of the cells can reveal the biochemical or biological mechanisms affected by radiation exposures. Predictive genomics has revolutionised how researchers can study the molecular basis of adverse effects of exposure to ionising radiation. It is expected that the new field will find efficient and high-throughput means to delineate mechanisms of action, risk assessment, identify and understand basic mechanisms that are critical to disease progression, and predict dose levels of radiation exposure. Previously, we have shown that cells responding to environmental toxicants through biological networks that are engaged in the regulation of molecular functions such as DNA repair and oxidative stress. To illustrate radiation genomics as an effective tool in biological dosimetry, an overview has been provided of some of the current radiation genomics landscapes as well as potential future systems to integrate the results of radiation response profiling across multiple biological levels in to a broad consensus picture. Predictive genomics represents a promising approach to high-throughput radiation biodosimetry.Defence Science Journal, 2011, 61(2), pp.133-137, DOI:http://dx.doi.org/10.14429/dsj.61.83

Telomere-mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients

Ataxia Telangiectasia Mutated Protein (ATM) is one of the first DNA damage sensors and is involved in telomere repair. Telomeres help maintain the stability of our chromosomes by protecting their ends from degradation. AT patients lacking the gene ATM are susceptible to acquire chromosomal anomalies and show heightened susceptibility to cancer. Here we show that cells from AT patients display considerable telomere attrition. Further, induced DNA damage and genomic instability were found to be more in DNA repair deficient ATM-/- cells (treated and untreated) than in normal cells. Results demonstrate that the cells ATM- deficient (heterozygous and homozygous) cells are sensitive to arsenite- and radiation-induced oxidative stress. Elevated numbers of chromosome alterations was seen in arsenic-treated and irradiated ATM-/- cells. The results might help in understanding the extent of susceptibility of AT patients to oxidative stress

Fungal systematics and evolution : FUSE 7

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Telomere-Mediated Chromosomal Instability Triggers TLR4 Induced Inflammation and Death in Mice

BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice) display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR) are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+), mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/-) mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups

Comparison of lymphocyte apoptotic index and qualitative DNA damage in yoga practitioners and breast cancer patients: A pilot study

Background: Yoga is found to be effective in reducing stress levels and radiation-induced DNA damage, and improving the quality of life, in breast cancer patients. The present study was aimed at comparing the apoptotic index (AI) and DNA damage of advanced yoga practitioners with those of breast cancer patients. Materials and Methods: This cross-sectional pilot study compared three groups (n = 9 each) of age-matched subjects viz. (1) Carcinoma breast patients in stage II or III undergoing radiation therapy after completing three cycles of chemotherapy; (2) Senior yoga practitioners who were practicing asanas, pranayama and meditation daily for more than 10 years; and (3) Normal healthy volunteers. Peripheral blood lymphocytes were isolated, and qualitative DNA damage (QDD) and AI were evaluated by single-cell gel electrophoresis assay. Approximately 500 cells were counted in each case. Number of cells that were normal, undergoing apoptosis, and with DNA damage were categorized and percentages were calculated. Results: Data being normally distributed, one-way analysis of variance (ANOVA) showed significant interaction between groups in AI (P = 0.016) and QDD (P = 0.045). On post-hoc analysis using Scheffe test, AI was significantly lower in non-yoga volunteers as compared with the breast cancer group (P = 0.019) and QDD was significantly lower in yoga practitioners when compared with non-yoga volunteers (P = 0.047). Conclusion: Cellular dysfunction (QDD) requires restorative mechanisms (AI) to restore the system to a balance. The results of this pilot study show trends, which indicate that in ill-health, there is inadequate restorative mechanisms (AI) although dysfunction (QDD) is high. Through regular practice of yoga, cellular dysfunction can be lowered, thus necessitating reduced restorative mechanisms. AI and QDD could also be useful indicators for predicting the three zones of health viz. disease, health, and positive health

Specific Role of Chk1 Phosphorylations in Cell Survival and Checkpoint Activation▿ †

Chk1 is a multifunctional protein kinase that plays essential roles in cell survival and cell cycle checkpoints. Chk1 is phosphorylated at multiple sites by several protein kinases, but the precise effects of these phosphorylations are largely unknown. Using a knockout-knockin system, we examined the abilities of Chk1 mutants to reverse the defects of Chk1-null cells. Wild-type Chk1 could rescue all the defects of Chk1-null cells. Like endogenous Chk1, wild-type Chk1 localized in both the cytoplasm and the nucleus, and its centrosomal association was enhanced by DNA damage. The mutation at S345 resulted in mitotic catastrophe, impaired checkpoints, and loss of the ability to localize in the cytoplasm, but the mutant retained the ability to be released from chromatin upon encountering genotoxic stressors. In contrast, the mutation at S317 resulted in impaired checkpoints and loss of chromatin release upon encountering genotoxic stressors, but its mutant retained the abilities to prevent mitotic catastrophes and to localize in the cytoplasm, suggesting the distinct effects of these phosphorylations. The forced immobilization of S317A/S345A in centrosomes resulted in the prevention of apoptosis in the presence or absence of DNA damage. Thus, two-step phosphorylation of Chk1 at S317 and S345 appeared to be required for proper localization of Chk1 to centrosomes

Telomere-mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients

Ataxia Telangiectasia Mutated Protein (ATM) is one of the first DNA damage sensors and is involved in telomere repair. Telomeres help maintain the stability of our chromosomes by protecting their ends from degradation. AT patients lacking the gene ATM are susceptible to acquire chromosomal anomalies and show heightened susceptibility to cancer. Here we show that cells from AT patients display considerable telomere attrition. Further, induced DNA damage and genomic instability were found to be more in DNA repair deficient ATM-/- cells (treated and untreated) than in normal cells. Results demonstrate that the cells ATM- deficient (heterozygous and homozygous) cells are sensitive to arsenite- and radiation-induced oxidative stress. Elevated numbers of chromosome alterations was seen in arsenic-treated and irradiated ATM-/- cells. The results might help in understanding the extent of susceptibility of AT patients to oxidative stress