DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1

DNA single-strand breaks (SSBs) are the commonest DNA lesions arising spontaneously in cells, and if not repaired may block transcription or may be converted into potentially lethal/clastogenic DNA double-strand breaks (DSBs). Recently, evidence has emerged that defects in the rapid repair of SSBs preferentially impact the nervous system. In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiesterase 1) protein and with a defect in repairing certain types of SSBs. Although SCAN1 is a rare neurodegenerative disorder, understanding the molecular basis of this disease will lead to better understanding of neurodegenerative processes. Here we review recent progress in our understanding of TDP1, single-strand break repair (SSBR), and neurodegenerative disease

BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells

Arsenic exposure constitutes one of the most widespread environmental carcinogens, and is associated with increased risk of many different types of cancers. Here we report that arsenite (As[III]) can induce both replication-dependent DNA double-strand breaks (DSB) and homologous recombination (HR) at doses as low as 5 µM (0.65 mg/l), which are within the typical doses often found in drinking water in contaminated areas. We show that the production of DSBs is dependent on active replication and is likely to be the result of conversion of a DNA single-strand break (SSB) into a toxic DSB when encountered by a replication fork. We demonstrate that HR is required for the repair of these breaks and show that a functional HR pathway protects against As[III]-induced cytotoxicity. In addition, BRCA2-deficient cells are sensitive to As[III] and we suggest that As[III] could be exploited as a therapy for HR-deficient tumours such as BRCA1 and BRCA2 mutated breast and ovarian cancers

Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks

Aberrant DNA replication is a primary cause of mutations that are associated with pathological disorders including cancer. During DNA metabolism, the primary causes of replication fork stalling include secondary DNA structures, highly transcribed regions and damaged DNA. The restart of stalled replication forks is critical for the timely progression of the cell cycle and ultimately for the maintenance of genomic stability. Our previous work has implicated the single-stranded DNA binding protein, hSSB1/NABP2, in the repair of DNA double-strand breaks via homologous recombination. Here, we demonstrate that hSSB1 relocates to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51. Consequently, hSSB1-depleted cells fail to repair and restart stalled replication forks. hSSB1 deficiency causes accumulation of DNA strand breaks and results in chromosome aberrations observed in mitosis, ultimately resulting in hSSB1 being required for survival to HU and camptothecin. Overall, our findings demonstrate the importance of hSSB1 in maintaining and repairing DNA replication forks and for overall genomic stability

Exercitatio Politica De Dicto M. T. Ciceronis, Quo Pacem Iniquam Iusto Bello Antefert

Quam Deo Auspice, Praeside ... Francisco Köhnen ... in Illustri Bremensium Gymnasio P P. Praeceptore ... Publico examini subiicit Henricus Aveman, Brunsvicensis. Ad diem 4 Februar. loco horisq[ue] solitisVorlageform des Erscheinungsvermerks: Bremae Typis Bertholdi & Henrici de Villiers, ibidem illustr. Gymnasii Typogr. Anno M DC LX

Letztes Denkmahl der Liebe bey dem allzufrühen Ableben Jhres hochgeschätzten Freundes Des Wohledlen und Wohlgelahrten Herrrn, Herrn Johann Paul Fladung, aus Salzungen, der Gottesgelahrheit rühmlichst Beflissenene, Welches den 10ten Juni 1756. erfolgte, aufgerichtet von des Wohlseeligen getreuen Freunden und Landesleuten. [G. E. C. Avemann, aus dem Meinungischen, b. R. B. G. A. Baumbach, aus dem Meinungischen, b. R. B. ...]

Gedächtnisgedicht auf Johann Paul Fladung, stud. theol., +10. Juni 1756Autopsie nach Exemplar der ULB Sachsen-AnhaltVorlageform des Erscheinungsvermerks: Jena, gedruckt bey Johann Friedrich Schill

Development of manufacturing process chains considering uncertainty

The production processes of forming companies are traditionally characterized by a high productivity. Process chains are developed with regard to cost efficiency for a predefined lot size. However, the accordingly determined optimal process chain might become inferior against the background of a changing company environment. This paper presents a feature-based methodology for the development of production process chains considering changeable company environments. A classification of influences on production processes is developed which allows the deduction of scenarios describing the interrelation between causes of change and companies’decision making criteria. Based on the value of the possibility to change or expand a process chain can be determined. The method is applied using the process chain planning for a particulate filter as an example