Grammar of protein domain architectures.

From an abstract, informational perspective, protein domains appear analogous to words in natural languages in which the rules of word association are dictated by linguistic rules, or grammar. Such rules exist for protein domains as well, because only a small fraction of all possible domain combinations is viable in evolution. We employ a popular linguistic technique, n-gram analysis, to probe the "proteome grammar"-that is, the rules of association of domains that generate various domain architectures of proteins. Comparison of the complexity measures of "protein languages" in major branches of life shows that the relative entropy difference (information gain) between the observed domain architectures and random domain combinations is highly conserved in evolution and is close to being a universal constant, at ∼1.2 bits. Substantial deviations from this constant are observed in only two major groups of organisms: a subset of Archaea that appears to be cells simplified to the limit, and animals that display extreme complexity. We also identify the n-grams that represent signatures of the major branches of cellular life. The results of this analysis bolster the analogy between genomes and natural language and show that a "quasi-universal grammar" underlies the evolution of domain architectures in all divisions of cellular life. The nearly universal value of information gain by the domain architectures could reflect the minimum complexity of signal processing that is required to maintain a functioning cell.

Crosstalk between the mitochondrial fission protein, Drp1, and the cell cycle is identified across various cancer types and can impact survival of epithelial ovarian cancer patients.

Mitochondrial metabolic reprogramming is a hallmark of tumorigenesis. Although mitochondrial function can impact cell cycle regulation it has been an understudied area in cancer research. Our study highlights a specific involvement of mitochondria in cell cycle regulation across cancer types. The mitochondrial fission process, which is regulated at the core by Drp1, impacts various cellular functions. Drp1 has been implicated in various cancer types with no common mechanism reported. Our Drp1-directed large-scale analyses of the publically available cancer genomes reveal a robust correlation of Drp1 with cell-cycle genes in 29 of the 31 cancer types examined. Hypothesis driven investigation on epithelial ovarian cancer (EOC) revealed that Drp1 co-expresses specifically with the cell-cycle module responsible for mitotic transition. Repression of Drp1 in EOC cells can specifically attenuate mitotic transition, establishing a potential casual role of Drp1 in mitotic transition. Interestingly, Drp1-Cell-Cycle co-expression module is specifically detected in primary epithelial ovarian tumors that robustly responded to chemotherapy, suggesting that Drp1 driven mitosis may underlie chemo-sensitivity of the primary tumors. Analyses of matched primary and relapsed EOC samples revealed a Drp1-based-gene-expression-signature that could identify patients with poor survival probabilities from their primary tumors. Our results imply that around 60% of platinum-sensitive EOC patients undergoing relapse show poor survival, potentially due to further activation of a mitochondria driven cell-cycle regime in their recurrent disease. We speculate that this patient group could possibly benefit from mitochondria directed therapies that are being currently evaluated at various levels, thus enabling targeted or personalized therapy based cancer management.