PARP1 catalytic variants reveal branching and chain length-specific functions of poly(ADP-ribose) in cellular physiology and stress response

Poly(ADP-ribosyl)ation regulates numerous cellular processes like genome maintenance and cell death, thus providing protective functions but also contributing to several pathological conditions. Poly(ADP-ribose) (PAR) molecules exhibit a remarkable heterogeneity in chain lengths and branching frequencies, but the biological significance of this is basically unknown. To unravel structure-specific functions of PAR, we used PARP1 mutants producing PAR of different qualities, i.e. short and hypobranched (PARP1\G972R), short and moderately hyperbranched (PARP1\Y986S), or strongly hyperbranched PAR (PARP1\Y986H). By reconstituting HeLa PARP1 knockout cells, we demonstrate that PARP1\G972R negatively affects cellular endpoints, such as viability, cell cycle progression and genotoxic stress resistance. In contrast, PARP1\Y986S elicits only mild effects, suggesting that PAR branching compensates for short polymer length. Interestingly, PARP1\Y986H exhibits moderate beneficial effects on cell physiology. Furthermore, different PARP1 mutants have distinct effects on molecular processes, such as gene expression and protein localization dynamics of PARP1 itself, and of its downstream factor XRCC1. Finally, the biological relevance of PAR branching is emphasized by the fact that branching frequencies vary considerably during different phases of the DNA damage-induced PARylation reaction and between different mouse tissues. Taken together, this study reveals that PAR branching and chain length essentially affect cellular functions, which further supports the notion of a ‘PAR code’

Validation of the Maudsley Addiction Profile Health Symptoms Scale as a Measure of Symptom Severity in Concurrent Mental Health and Substance Use Disorder Inpatients

The Maudsley Addiction Profile is often used in research on concurrent disorders (comorbid mental health and substance use disorders). However, its Health Symptoms Scale (MAP-HSS) has not been validated and psychological and somatic mental health symptom severity scores from this measure are rarely reported. In this study, the concurrent validity of the MAP-HSS was assessed via correlations with the Symptom Checklist-90-Revised. The MAP-HSS had acceptable concurrent validity (rho’s = 0.717-0.781, p’s < 0.001) and internal consistency (a = 0.934). The validity of the MAP-HSS supports its utility as a measure of overall psychological wellbeing in research with concurrent disorder populations.Arts, Faculty ofMedicine, Faculty ofPsychiatry, Department ofPsychology, Department ofUnreviewedFacultyGraduateUndergraduat

Integrative Verknüpfung von Studium und Praxis am Leuphana College

Hellmann K, Teigeler M, Seifert A. Integrative Verknüpfung von Studium und Praxis am Leuphana College. In: Beck K, Bothe T, Glaser T, Heuer C, Schütz J, Seifert A, eds. Bildung und Hochschule. Impulse für Studium und Lehre am Beispiel des Leuphana College. Münster: Waxmann; 2016: 205-216

PARP1 catalytic variants reveal branching and chain length-specific functions of poly(ADP-ribose) in cellular physiology and stress response

Poly(ADP-ribosyl)ation regulates numerous cellular processes like genome maintenance and cell death, thus providing protective functions but also contributing to several pathological conditions. Poly(ADP-ribose) (PAR) molecules exhibit a remarkable heterogeneity in chain lengths and branching frequencies, but the biological significance of this is basically unknown. To unravel structure-specific functions of PAR, we used PARP1 mutants producing PAR of different qualities, i.e. short and hypobranched (PARP1\G972R), short and moderately hyperbranched (PARP1\Y986S), or strongly hyperbranched PAR (PARP1\Y986H). By reconstituting HeLa PARP1 knockout cells, we demonstrate that PARP1\G972R negatively affects cellular endpoints, such as viability, cell cycle progression and genotoxic stress resistance. In contrast, PARP1\Y986S elicits only mild effects, suggesting that PAR branching compensates for short polymer length. Interestingly, PARP1\Y986H exhibits moderate beneficial effects on cell physiology. Furthermore, different PARP1 mutants have distinct effects on molecular processes, such as gene expression and protein localization dynamics of PARP1 itself, and of its downstream factor XRCC1. Finally, the biological relevance of PAR branching is emphasized by the fact that branching frequencies vary considerably during different phases of the DNA damage-induced PARylation reaction and between different mouse tissues. Taken together, this study reveals that PAR branching and chain length essentially affect cellular functions, which further supports the notion of a 'PAR code'.publishe

Nutrient enrichment increases invertebrate herbivory and pathogen damage in grasslands

Plant damage by invertebrate herbivores and pathogens influences the dynamics of grassland ecosystems, but anthropogenic changes in nitrogen and phosphorus availability can modify these relationships. Using a globally distributed experiment, we describe leaf damage on 153 plant taxa from 27 grasslands worldwide, under ambient conditions and with experimentally elevated nitrogen and phosphorus. Invertebrate damage significantly increased with nitrogen addition, especially in grasses and non-leguminous forbs. Pathogen damage increased with nitrogen in grasses and legumes but not forbs. Effects of phosphorus were generally weaker. Damage was higher in grasslands with more precipitation, but climatic conditions did not change effects of nutrients on leaf damage. On average, invertebrate damage was relatively higher on legumes and pathogen damage was relatively higher on grasses. Community-weighted mean damage reflected these functional group patterns, with no effects of N on community-weighted pathogen damage (due to opposing responses of grasses and forbs) but stronger effects of N on community-weighted invertebrate damage (due to consistent responses of grasses and forbs). Synthesis. As human-induced inputs of nitrogen and phosphorus continue to increase, understanding their impacts on invertebrate and pathogen damage becomes increasingly important. Our results demonstrate that eutrophication frequently increases plant damage and that damage increases with precipitation across a wide array of grasslands. Invertebrate and pathogen damage in grasslands is likely to increase in the future, with potential consequences for plant, invertebrate and pathogen communities, as well as the transfer of energy and nutrients across trophic levels.</p