Taming the tiger by the tail: modulation of DNA damage responses by telomeres

Telomeres are by definition stable and inert chromosome ends, whereas internal chromosome breaks are potent stimulators of the DNA damage response (DDR). Telomeres do not, as might be expected, exclude DDR proteins from chromosome ends but instead engage with many DDR proteins. However, the most powerful DDRs, those that might induce chromosome fusion or cell-cycle arrest, are inhibited at telomeres. In budding yeast, many DDR proteins that accumulate most rapidly at double strand breaks (DSBs), have important functions in physiological telomere maintenance, whereas DDR proteins that arrive later tend to have less important functions. Considerable diversity in telomere structure has evolved in different organisms and, perhaps reflecting this diversity, different DDR proteins seem to have distinct roles in telomere physiology in different organisms. Drawing principally on studies in simple model organisms such as budding yeast, in which many fundamental aspects of the DDR and telomere biology have been established; current views on how telomeres harness aspects of DDR pathways to maintain telomere stability and permit cell-cycle division are discussed

Untersuchungen zu Nahrungsquellen und Nahrungsbeziehungen im Pantanal von Mato Grosso

Die dieser Dissertation zugrunde liegenden Arbeiten wurde im Rahmen des Pantanal-Ecology-Projects der Universität von Cuiabá, Brasilien in Zusammenarbeit mit dem Max-Planck-Institut für Limnologie, Plön, durchgeführt. Die Dissertation basiert auf drei Manuskripten, die bei internationalen Zeitschriften zur Veröffentlichung eingereicht wurden. Mit einer Kombination aus Freilandexperimenten und einer Sammlung von Freilanddaten sollen die Nahrungsquellen von aquatischen Konsumenten des Überschwemmungsgebietes Pantanal von Mato Grosso, Brasilien beleuchtet werden. Dazu wurde die Methode der Messung der stabilen Isotopen-Verhältnisse des Kohlenstoffs (δ¹³C) und des Stickstoffs (δ¹⁵N) angewandt. Experimente zeigten, dass die δ¹³C Werte von Makrophyten während des Abbaus stabil bleiben, während die δ¹⁵N Werte großen Variationen ausgesetzt sind. Diese Veränderungen wurden auf mikrobielle Aktivitäten zurückgeführt. Es wurden Fütterungsexperimente mit den im Untersuchungsgebiet weitverbreiteten Apfelschnecken Pomacea lineata durchgeführt. Deren Ergebnisse und die Freilanddaten geben Hinweise darauf, dass die Schnecken sich scheinbar nicht von der vorherrschenden Makrophyten-Familie Pontederiaceae ernähren. Das C₄ Gras Paspalum repens ist Bestandteil ihrer Nahrung. Das partikuläre organische Material stellt ein reichlichen Nahrungsvorrat für aquatische Herbivore dar. Die Zusammensetzung des POM unterscheidet sich je nach hydrologischer Jahreszeit und StandortInhaltsverzeichnis I Danke III Zusammenfassung V Liste der Publikationen IX A EINFÜHRUNG 1 1. Das Pantanal 1 1.1. Das Pantanal-Ökologie-Projekt 1 1.2. Das Untersuchungsgebiet 4 2. Methodische Aspekte 9 2.1. Definition der Stabilen Isotope 9 2.2. Messung der Verhältnisse Stabiler Isotope 9 2.3. Die Fraktionierung der Stabilen Isotope 12 2.4. Die natürlichen Isotopen-Verhältnisse an der Basis des Nahrungskette 13 3. Die Anwendung der Messung der stabilen Isotopen-Verhältnisse bei ökologischen Fragestellungen 17 4. Kenntnisstand und Zielstellung der Publikationen 19 B ZUSAMMENFASSUNG DER PUBLIKATIONEN 23 1. Ergebnisse und Diskussion 23 2. Schlussfolgerungen und Ausblick 33 Literaturverzeichnis 35 C DIE PUBLIKATIONEN 44 Publikation I: 45 Publikation II: 65 Publikation III: 8

Feeding and growth of apple snail Pomacea lineata in the Pantanal wetland, Brazil - a stable isotope approach

Apple snails Pomacea lineata (SPIX 1827) are widespread in the tropical regions of Brazil as well as in the Pantanal wetland of Mato Grosso in the western part of the country. They have a key position in the Pantanal food web and serve as food for many animals e.g. fishes, birds, and caimans. However, little is known about their feeding preferences and growth rates. Stable isotopes have been used successfully on numerous studies as food source indicator. Therefore, the i15N and i13C values of snails from 0.45 to 3.03vcm in length, which were collected in the rainy season from March through May, were analyzed. Snails signatures revealed ambiguous evidence for food preferences. i15N and i13C values ranged between m2.8 and 12.4‰ and between m24.2 and m16.4‰, respectively. This range of values mirrors the highly variable isotope values of possible food sources comprising C3 and C4 macrophytes. To test whether all common food sources were similarly assimilated, feeding experiments with different diets were conducted. Snail eggs were reared in tanks and offered different but single plants. Snails fed different diets and i13C values of the food were reflected in the animal tissue. Growth varied considerably in experiments with different diets indicating the preference for certain food sources. Also, the fractionation of nitrogen isotopes between food and animal varied from 0.1 to 17.0‰. The results are explained by different feeding habits, and it is supposed that animals fed either on the plant itself or on bacteria mats growing in the tanks. In an additional experiment juvenile snails were offered one single food with a distinctive C4 grass signature. These snails did not grow detectably, but nevertheless isotope signatures approached to values of the diet

Stable carbon and nitrogen signatures of decomposing tropical macrophytes

The Pantanal of Mato Grosso, Brazil, is a large, seasonal wetland, which exhibits high macrophyte productivity at the beginning of the rainy season, when the floodplain becomes flooded. During inundation, from December through May, there is rapid turnover of decomposing macrophyte litter, which is subsequently colonized and consumed by various organisms. In this paper, the variation in the carbon and nitrogen isotope signatures of decomposing macrophytes and detritus was determined to provide an isotopic baseline for the elucidation of higher trophic levels. Seven abundant macrophyte species, Cyperaceae sp., Pontederia lanceolata, Cabomba furcata, Salvinia auriculata, Eichhornia crassipes, Nymphaea amazonum and Paspalum repens, were exposed in mesocosm decomposition experiments lasting 21 or 100 days. Stable isotope ratios of carbon and nitrogen and the atomic C/N ratios were determined for decomposing plant material, particulate organic matter (POM), the microbial film, and aquatic invertebrate larvae. The delta(13)C values for the macrophytes did not change during decomposition. However, the variability of delta(15)N was high (range of +/- 6parts per thousand) due to microbial activity. There was no consistent difference in the isotopic signatures of macrophytes and POM. C/N ratios decreased from 17 to 50 in macrophytes, to 7 to 12 in POM. The isotopic signatures and C/N ratios of the microbial film were the same as those of POM. We concluded that heterotrophic processes did not fractionate stable carbon isotopes but caused an increase in the variability of stable nitrogen ratios and a change in the C/N ratios in our experimental system. Therefore, it was not possible to distinguish fresh and senescent material or even POM when used as a food source. The delta(13)C values of the aquatic larvae were closely coupled to those of the carbon source provided

Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism

Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P < 0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n = 480) and matched controls (n = 480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P = 0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype