Swain, A. | Search bioRxiv

bioRxiv2018

Effect of ring topology in a stochastic model for Z-ring dynamics in bacteria

Understanding the mechanisms responsible for dynamics of the Z-ring is important for our understanding of cell division in prokaryotic cells. In this work, we present a minimal stochastic model that qualititatively reproduces observations of polymerization, of formation of dynamic contractile ring that is stable for a long time and of depolymerization shown by FtsZ polymer. We explore different mechanisms for ring breaking and hydrolysis. Hydrolysis is known to regulate the dynamics of other tubulin polymers like microtubules. We find that the presence of the ring allows for an additional mechanism for regulating the dynamics of FtsZ polymers. Ring breaking dynamics in the presence of hydrolysis naturally induce rescue and catastrophe events, irrespective of the mechanism of hydrolysis. Based on our model, we conclude that the Z-ring undergoes random breaking and closing during the process of cell division.

biophysics↗

bioRxiv2017

Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance

PARP inhibitors (PARPi) target homologous recombination defective tumour cells via synthetic lethality. Genome-wide and high-density CRISPR-Cas9 \"tag, mutate and enrich\" mutagenesis screens identified single amino acid mutations in PARP1 that cause profound PARPi-resistance. These included PARP1 mutations outside of the DNA interacting regions of the protein, such as mutations in solvent exposed regions of the catalytic domain and clusters of mutations around points of contact between ZnF, WGR and HD domains. These mutations altered PARP1 trapping, as did a mutation found in a clinical case of PARPi resistance. These genetic studies reinforce the importance of trapped PARP1 as a key cytotoxic DNA lesion and suggest that interactions between non-DNA binding domains of PARP1 influence cytotoxicity. Finally, different mechanisms of PARPi resistance (BRCA1 reversion, PARP1, 53BP1, REV7 mutation) had differing effects on chemotherapy sensitivity, suggesting that the underlying mechanism of PARPi resistance likely influences the success of subsequent therapies.

cancer biology↗