Global Genome Responses to DNA-Repair Deficiency Modulate Aging and Stress Response Pathways

The genomes of all animals are constantly challenged by exogenous and endogenous sources of DNA damaging agents. UV radiation, chemicals, pollutants, and by-products of the cells’ own metabolism may damage the genetic material. Such damages are harmful to the animal as they may cause mutations or generate cytotoxic lesions, which in turn may lead to disease, cancer and aging. Protection of the genome is therefore of the utmost importance. To counteract such potential detrimental effects, all organisms have developed protective mechanisms such as antioxidants and DNA repair mechanisms. DNA excision repair proteins detect lesions in DNA, excise the damaged base and re-insert a correct base, thus maintaining the correct coding properties of the genome. Defects in DNA repair mechanisms may lead to cancer, neurodegeneration, other age-related pathologies or senescence. The nematode Caenorhabditis elegans (C. elegans) contains very few DNA glycosylases, which are the lesion-detecting proteins in DNA excision repair, compared to other animals and organisms. Analysis of all transcribed genes in DNA repair-deficient mutants in C. elegans revealed a global transcriptional response aimed at minimizing further damage to the genome. This involved a down-regulation of insulin-like signaling and an upregulation of antioxidants and stress response genes, similar to the response seen in both long-lived and old animals. This response seems to be conserved across different species as analysis of comparable mutants in the yeast Saccharomyces cerevisiae and mouse showed a similar response. Pathway reconstruction and literature mining suggests that this response is not elicited only by lack of repair per se, but rather from aberrant or attempted processing of lesions by other repair pathways than those normally repairing such lesions. This result in lesions that block the transcription of active genes and signal the transcription of other genes aimed at reducing further damage to DNA. Analysis of C. elegans mutants deficient in two different repair pathways revealed a completely different response with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as downregulation of other DNA repair pathways. The mechanism and signaling origin of this response is yet unknown. Gene expression profiling is emerging as a powerful complementary tool to classical genetics and molecular analysis. By taking a systems biology approach, which takes into account the interplay between many pathways, gene expression profiling may aid in the interpretation of observed phenotypes and assist in the generation of new testable hypotheses

A Two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways

Activation of oxidative stress-responses and downregulation of insulin-like signaling (ILS) is seen in Nucleotide Excision Repair (NER) deficient segmental progeroid mice. Evidence suggests that this is a survival response to persistent transcription-blocking DNA damage, although the relevant lesions have not been identified. Here we show that loss of NTH-1, the only Base Excision Repair (BER) enzyme known to initiate repair of oxidative DNA damage inC. elegans, restores normal lifespan of the short-lived NER deficient xpa-1 mutant. Loss of NTH-1 leads to oxidative stress and global expression profile changes that involve upregulation of genes responding to endogenous stress and downregulation of ILS. A similar, but more extensive, transcriptomic shift is observed in the xpa-1 mutant whereas loss of both NTH-1 and XPA-1 elicits a different profile with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as DNA repair and DNA damage response genes. The restoration of normal lifespan and absence oxidative stress responses in nth-1;xpa-1 indicate that BER contributes to generate transcription blocking lesions from oxidative DNA damage. Hence, our data strongly suggests that the DNA lesions relevant for aging are repair intermediates resulting from aberrant or attempted processing by BER of lesions normally repaired by NER

Turbulent Skies - A Case Study of SAS Braathens

Title: Turbulent Skies – A Case Study of SAS Braathens Date of seminar: 1st June 2006. Course: BUS 809. Master Thesis in International Marketing & Brand Management, 15 ECTS-credits. Authors: Jørgen Fensgård and Christian Larsen. Advisor: Frans Melin, Assistant Professor, Department of Business Administration, School of Economics and Management, Lund University, Sweden. Keywords: SAS Braathens, mergers and acquisitions, employee behaviour, service quality, internal branding. Thesis purpose: The objective of this master thesis is to analyse employee behaviour in mergers and acquisitions in order to understand how opposing values might affect the delivery of desired service quality. A second objective of this thesis is to create a case meant for learning situations based on the study undertaken. Methodology: The research has a social constructionism point of view in order to understand how employee behaviour is affected by opposing values. A combination of case study and history research design was chosen in order to study historical data from the early stage of the merger between SAS and Braathens. Data was collected from a database (Retriever) containing more than 5 million articles from the 21 largest and most important newspapers in Norway. More than 7000 articles were scanned through headline and abstract in order to find the most relevant information. An unstructured interview was conducted with pilots in cockpit by one of the authors on a SAS Braathens-flight. Theoretical perspective: Theory starts by explaining the human aspects and reactions in mergers and acquisitions. Further service management is discussed together with the importance of employee behaviour and alignment of values in service businesses. At last the definition and concept of internal branding is discussed in order to be seen in relation to mergers and acquisitions. Empirical data: Case study of SAS Braathens conducted through a document study. Conclusions: Opposing values affect employee behaviour through affecting and strengthening psychological effects. Opposing values hinder employees to deliver the organizations desired service quality due to anxiety, distress, anger and frustration. Internal branding explained as an effective tool in aligning values in mergers and acquisitions. Consistency needed to acculturate and align the organizational cultures

Global transcriptional response after exposure of fission yeast cells to ultraviolet light

Background In many cell types, including the fission yeast Schizosaccharomyces pombe, a set of checkpoints are induced by perturbations of the cell cycle or by DNA damage. Many of the checkpoint responses include a substantial change of the transcriptional pattern. As part of characterising a novel G1/S checkpoint in fission yeast we have investigated whether a transcriptional response is induced after irradiation with ultraviolet light. Results Microarray analyses were used to measure the global transcription levels of all open reading frames of fission yeast after 254 nm ultraviolet irradiation, which is known to induce a G1/S checkpoint. We discovered a surprisingly weak transcriptional response, which is quite unlike the marked changes detected after some other types of treatment and in several other checkpoints. Interestingly, the alterations in gene expression after ultraviolet irradiation were not similar to those observed after ionising radiation or oxidative stress. Pathway analysis suggests that there is little systematic transcriptional response to the irradiation by ultraviolet light, but a marked, coordinated transcriptional response was noted on progression of the cells from G1 to S phase. Conclusion There is little response in fission yeast to ultraviolet light at the transcriptional level. Amongst the genes induced or repressed after ultraviolet irradiation we found none that are likely to be involved in the G1/S checkpoint mechanism, suggesting that the checkpoint is not dependent upon transcriptional regulation

Global transcriptional response after exposure of fission yeast cells to ultraviolet light

Abstract Background In many cell types, including the fission yeast Schizosaccharomyces pombe, a set of checkpoints are induced by perturbations of the cell cycle or by DNA damage. Many of the checkpoint responses include a substantial change of the transcriptional pattern. As part of characterising a novel G1/S checkpoint in fission yeast we have investigated whether a transcriptional response is induced after irradiation with ultraviolet light. Results Microarray analyses were used to measure the global transcription levels of all open reading frames of fission yeast after 254 nm ultraviolet irradiation, which is known to induce a G1/S checkpoint. We discovered a surprisingly weak transcriptional response, which is quite unlike the marked changes detected after some other types of treatment and in several other checkpoints. Interestingly, the alterations in gene expression after ultraviolet irradiation were not similar to those observed after ionising radiation or oxidative stress. Pathway analysis suggests that there is little systematic transcriptional response to the irradiation by ultraviolet light, but a marked, coordinated transcriptional response was noted on progression of the cells from G1 to S phase. Conclusion There is little response in fission yeast to ultraviolet light at the transcriptional level. Amongst the genes induced or repressed after ultraviolet irradiation we found none that are likely to be involved in the G1/S checkpoint mechanism, suggesting that the checkpoint is not dependent upon transcriptional regulation.</p

DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals

Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans. We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling. Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced in NER mutants that are also impaired in their response to ionizing radiation and inter-strand crosslinks. These results suggest that multiple DNA-repair pathways can protect against replicative decline and indicate that there might be a direct link between the severity of symptoms and the level of DNA-repair deficiency in patients.Cell Death and Differentiation advance online publication, 6 September 2013; doi:10.1038/cdd.2013.126