Bringing It All Together: Coupling Excision Repair to the DNA Damage Checkpoint

Nucleotide excision repair and the ATR-mediated DNA damage checkpoint are two critical cellular responses to the genotoxic stress induced by ultraviolet (UV) light and are important for cancer prevention. In vivo genetic data indicate that these global responses are coupled. Aziz Sancar et al. developed an in vitro coupled repair-checkpoint system to analyze the basic steps of these DNA damage stress responses in a biochemically defined system. The minimum set of factors essential for repair-checkpoint coupling include damaged DNA, the excision repair factors (XPA, XPC, XPF-ERCC1, XPG, TFIIH, RPA), the 5'-3' exonuclease EXO1, and the damage checkpoint proteins ATR-ATRIP and TopBP1. This coupled repair-checkpoint system was used to demonstrate that the ~30 nucleotide single-stranded DNA (ssDNA) gap generated by nucleotide excision repair is enlarged by EXO1 and bound by RPA to generate the signal that activates ATR

Telomere Regulation in Arabidopsis thaliana by the CST Capping Complex and DNA Damage Response Proteins

The ends of chormosomes are capped by telomeres, which distinguish the termini from damaged DNA. Paradoxically, DNA repair proteins are also required for telomere maintenance. How DNA repair pathways are regulated to maintain telomeres while remaining competent to repair DNA damage throughout the genome is unknown. In this dissertation, I used a genetic approach to investigate how critical components of telomerase and the telomere protein complex interact with the DNA damage response (DDR). In the flowering plant, Arabidopsis thaliana telomeres are bound by the CST (CTC1/STN1/TEN1) heterotrimer. Loss of any CST component results in telomere shortening, telomere fusions, increased G-overhang length and telomere recombination. To understand the phenotypes caused by CST deficiency, I examined telomeres from plants lacking CTC1 or STN1 and TERT or KU. My analysis showed that CST acts in a separate genetic pathway for telomere length regulation from both KU and TERT. Further, I found that KU and CST act in separate genetic pathways for regulation of G-overhang formation. These demonstrate that multiple pathways are used to maintain telomere length and architecture in plants. My study of the interaction of telomere components with the DDR revealed ATR promotes genome stability and telomere length maintenance in the absence of CTC1, probably by activating programmed cell death of stem cells with high amounts of DNA damage. I also found that poly(ADP-ribosylation) is not required for maintenance of Arabidopsis telomeres, in contrast to human telomeres. Finally, I found an unexpected connection between the DDR and telomerase. My research showed that ATR maintains telomerase activity levels. Further, induction of double- stranded DNA breaks in seedlings led to a rapid decrease in telomerase activity, which correlated with increased abundance of TER2, an alternate Arabidopsis telomerase RNA. I hypothesize that TER2 inhibits telomerase to prevent its inappropriate action at internal sites in chromosomes. These data reveal two ways that DDR pathways work in concert with telomerase to promote genome integrity

Stationary shapes of deformable particles moving at low Reynolds numbers

Lecture Notes of the Summer School ``Microswimmers -- From Single Particle Motion to Collective Behaviour'', organised by the DFG Priority Programme SPP 1726 (Forschungszentrum J{\"{u}}lich, 2015).Comment: Pages C7.1-16 of G. Gompper et al. (ed.), Microswimmers - From Single Particle Motion to Collective Behaviour, Lecture Notes of the DFG SPP 1726 Summer School 2015, Forschungszentrum J\"ulich GmbH, Schriften des Forschungszentrums J\"ulich, Reihe Key Technologies, Vol 110, ISBN 978-3-95806-083-

Elaborated Modeling of Synchrotron Motion in Vlasov-Fokker-Planck Solvers

Solving the Vlasov-Fokker-Planck equation is a well-tested approach to simulate dynamics of electron bunches self-interacting with their own wake-field. Typical implementations model the dynamics of a charge density in a damped harmonic oscillator, with a small perturbation due to collective effects. This description imposes some limits to the applicability: Because after a certain simulation time coherent synchrotron motion will be damped down, effectively only the incoherent motion is described. Furthermore – even though computed - the tune spread is typically masked by the use of a charge density instead of individual particles. As a consequence, some effects are not reproduced. In this contribution, we present methods that allow to consider single-particle motion, coherent synchrotron oscillations, non-linearities of the accelerating voltage, higher orders of the momentum compaction factor, as well as modulations of the accelerating voltage. We also provide exemplary studies – based on the KIT storage ring KARA (KArlsruhe Research Accelerator) - to show the potentiality of the methods