Metabolic reprogramming has been proposed to be a hallmark of cancer, yet we currently lack a systematic characterization of the metabolic pathways active in transformed cells. Using mass spectrometry, we measured the consumption and release (CORE) of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated CORE profiles with a pre-existing atlas of gene expression. The integrated analysis identified glycine consumption and expression of the mitochondrial glycine biosynthetic pathway as strongly correlated with rates of proliferation across cancer cells. Antagonizing glycine uptake and its mitochondrial biosynthesis preferentially impaired rapidly proliferating cells. Moreover, higher expression of this pathway was associated with greater mortality in breast cancer patients. Increased reliance on glycine may represent a metabolic vulnerability for selectively targeting rapid cancer cell proliferation.

A longstanding question in biology is whether there is an intrinsic mechanism for coordinating growth and cell cycle in metazoan cells. We have examined cell size distributions in populations of lymphoblasts and applied a novel mathematical analysis to calculate accurately how growth rates vary with both cell size and the cell cycle. Our results show that growth rate is size-dependent throughout the cell cycle. After initial growth suppression there is a rapid increase in growth rate in G1, followed by a constant exponential growth phase. The probability of cell division varies independently with cell size and cell age. We conclude that proliferating mammalian cells have an intrinsic mechanism that maintains cell size.

Different animal cell types have distinctive and characteristic sizes. How a particular cell size is specified by differentiation programs and physiology remains one of the fundamental unknowns in cell biology. In this review we explore the evidence that individual cells autonomously sense and specify their own size. We discuss possible mechanisms by which size sensing and size specification may take place. Finally, we explore the physiological implications of size control. Why is it important that particular cell types maintain a particular size? We develop these questions by examination of current literature and pose the questions that we anticipate will guide this field in the upcoming years.

Biologists have long been concerned about what constrains variation in cell size; yet, progress on this question has been slow and stymied by experimental limitations1. We describe a new method, ergodic rate analysis (ERA), that uses single cell measurements of fixed steady-state populations to accurately infer the rates of molecular events, including rates of cell growth. ERA exploits the fact that the number of cells in a particular state is related to the average transit time through that state2. With this method, one can calculate full time trajectories of any feature that can be labeled fixed cells, for example levels of phospho-proteins or total cellular mass. Using ERA we find evidence for a size-discriminatory process at the G1/S transition that acts to decrease cell-to-cell size variation.

Summary DNA double strand breaks are repaired by two main pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). The choice between these pathways depends on cell cycle phase; however the continuous effect of cell cycle on the balance between them is still unclear. We used live cell imaging and fluorescent reporters for 53BP1, Rad52 and cell cycle to quantify the relative contribution of NHEJ and HR at different points of the cell cycle in single cells. We found that NHEJ is the dominant repair pathway in G1 and G2 even when both repair pathways are functional. The shift from NHEJ to HR is gradual, with the highest proportion of breaks repaired by HR in mid-S, where amount of DNA replication is highest. Higher proportions of HR also strongly correlate with slower rates of repair. Our study shows that the choice of repair mechanism is continuously adjusted throughout the cell cycle and suggests that the extent of active replication, rather than the presence of a sister chromatid influences the balance between the two repair pathways in human cells.

A key question in molecular genetics is why severe mutations often do not result in a detectably abnormal phenotype. This robustness was partially ascribed to redundant paralogs that may provide backup for one another in case of mutation. Mining mutant viability and mRNA expression data in Saccharomyces cerevisiae, we found that backup was provided predominantly by paralogs that are expressed dissimilarly in most growth conditions. We considered that this apparent inconsistency might be resolved by a transcriptional reprogramming mechanism that allows the intact paralog to rescue the organism upon mutation of its counterpart. We found that in wild-type cells, partial coregulation across growth conditions predicted the ability of paralogs to alter their transcription patterns and to provide backup for one another. Notably, the sets of regulatory motifs that controlled the paralogs with the most efficient backup activity deliberately overlapped only partially; paralogs with highly similar or dissimilar sets of motifs had suboptimal backup activity. Such an arrangement of partially shared regulatory motifs reconciles the differential expression of paralogs with their ability to back each other up.

Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes. One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses. Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime. In contrast, numerous reports describe instances of functional overlaps that have been conserved throughout extended evolutionary periods. More interestingly, many such backed-up genes were shown to be transcriptionally responsive to the intactness of their redundant partner and are up-regulated if the latter is mutationally inactivated. By manual inspection of the literature, we have compiled a list of such ''responsive backup circuits'' in a diverse list of species. Reviewing these responsive backup circuits, we extract recurring principles characterizing their regulation. We then apply modeling approaches to explore further their dynamic properties. Our results demonstrate that responsive backup circuits may function as ideal devices for filtering nongenetic noise from transcriptional pathways and obtaining regulatory precision. We thus challenge the view that such redundancies are simply leftovers of ancient duplications and suggest they are an additional component to the sophisticated machinery of cellular regulation. In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.evolution ͉ gene duplications ͉ modeling ͉ systems biology ͉ noise

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell’s target size.