Intracellular crowding effects on the self-association of the bacterial cell division protein FtsZ.

The dimerization rate of the bacterial cell division protein FtsZ is strongly affected by the intracellular crowding. Yet the complexity of the intracellular environment makes it difficult to investigate via all-atom molecular dynamics or other detailed theoretical methods. We study the crowding effect on FtsZ dimerization which is the first step of an oligomerization process that results in more elaborate supramolecular structures. In particular, we consider the effect of intracellular crowding on the reaction rates, and their dependence on the different concentrations of crowding agents. We achieved this goal by using Brownian dynamics (BD) simulation techniques and a modified post-processing approach in which we decompose the rate constant in crowded media as a product of the rate constant in the dilute solution times a factor that incorporates the crowding effect. The latter factor accounts for the diffusion reduction and crowder induced energy. In addition we include the crowding effects on water viscosity in the BD simulations of crowded media. We finally show that biomolecular crowding has a considerable effect on the FtsZ dimerization by increasing the dimerization rate constant from 2.6×10(7)M(-1)s(-1) in the absence of crowders to 1.0×10(8)M(-1)s(-1) at crowding level of 0.30.

Cross-species identification of cancer resistance-associated genes that may mediate human cancer risk.

Cancer is a predominant disease across animals. We applied a comparative genomics approach to systematically characterize genes whose conservation levels correlate positively (PC) or negatively (NC) with cancer resistance estimates across 193 vertebrates. Pathway analysis reveals that NC genes are enriched for metabolic functions and PC genes in cell cycle regulation, DNA repair, and immune response, pointing to their corresponding roles in mediating cancer risk. We find that PC genes are less tolerant to loss-of-function (LoF) mutations, are enriched in cancer driver genes, and are associated with germline mutations that increase human cancer risk. Their relevance to cancer risk is further supported via the analysis of mouse functional genomics and cancer mortality of zoo mammals' data. In sum, our study describes a cross-species genomic analysis pointing to candidate genes that may mediate human cancer risk.

Expanded CUG Repeats Trigger Disease Phenotype and Expression Changes through the RNAi Machinery in C. elegans.

Myotonic dystrophy type 1 is an autosomal-dominant inherited disorder caused by the expansion of CTG repeats in the 3' untranslated region of the DMPK gene. The RNAs bearing these expanded repeats have a range of toxic effects. Here we provide evidence from a Caenorhabditis elegans myotonic dystrophy type 1 model that the RNA interference (RNAi) machinery plays a key role in causing RNA toxicity and disease phenotypes. We show that the expanded repeats systematically affect a range of endogenous genes bearing short non-pathogenic repeats and that this mechanism is dependent on the small RNA pathway. Conversely, by perturbating the RNA interference machinery, we reversed the RNA toxicity effect and reduced the disease pathogenesis. Our results unveil a role for RNA repeats as templates (based on sequence homology) for moderate but constant gene silencing. Such a silencing effect affects the cell steady state over time, with diverse impacts depending on tissue, developmental stage, and the type of repeat. Importantly, such a mechanism may be common among repeats and similar in human cells with different expanded repeat diseases.