Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks

The gene regulatory network (GRN) is the central decision‐making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large‐scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. DOI: http://dx.doi.org/10.7554/eLife.02863.00

Superhydrophobicity on hairy surfaces

We investigate the wetting properties of surfaces patterned with fine elastic hairs, with an emphasis on identifying superhydrophobic states on hydrophilic hairs. We formulate a two dimensional model of a large drop in contact with a row of equispaced elastic hairs and, by minimising the free energy of the model, identify the stable and metastable states. In particular we concentrate on "partially suspended" states, where the hairs bend to support the drop -- singlet states where all hairs bend in the same direction, and doublet states where neighbouring hairs bend in opposite directions -- and find the limits of stability of these configurations in terms of material contact angle, hair flexibility, and system geometry. The drop can remain suspended in a singlet state at hydrophilic contact angles, but doublets exist only when the hairs are hydrophobic. The system is more likely to evolve into a singlet state if the hairs are inclined at the root. We discuss how, under limited circumstances, the results can be modified to describe an array of hairs in three dimensions. We find that now both singlets and doublets can exhibit superhydrophobic behaviour on hydrophilic hairs. We discuss the limitations of our approach and the directions for future work

3 tera-basepairs as a fundamental limit for robust DNA replication

10 p.-2 tab.In order to maintain functional robustness and species integrity, organisms must ensure high fidelity of the genome duplication process. This is particularly true during early development, where cell division is often occurring both rapidly and coherently. By studying the extreme limits of suppressing DNA replication failure due to double fork stall errors, we uncover a fundamental constant that describes a trade-off between genome size and architectural complexity of the developing organism. This constant has the approximate value N_U ≈ 3×10^12 basepairs, and depends only on two highly conserved molecular properties of DNA biology. We show that our theory is successful in interpreting a diverse range of data across the Eukaryota.MAM, LA and TJN acknowledge prior support from the Scottish Universities Life Sciences Alliance. JJB acknowledges support from Cancer Research UK (grant C303/A14301) and the Wellcome Trust (grant WT096598MA). TJN acknowledges prior support from the National Institutes of Health (Physical Sciences in Oncology Centers, U54 CA143682).Peer reviewe

Defects in the origin licensing checkpoint stresses cells exiting G0

The full licensing of replication origins in late G1 is normally enforced by the licensing checkpoint. In this issue, Matson et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201902143) show that this checkpoint is inoperative in cells exiting from G0, resulting in incomplete origin licensing and consequent replicative stress

The contribution of dormant origins to genome stability:from cell biology to human genetics

AbstractThe ability of a eukaryotic cell to precisely and accurately replicate its DNA is crucial to maintain genome stability. Here we describe our current understanding of the process by which origins are licensed for DNA replication and review recent work suggesting that fork stalling has exerted a strong selective pressure on the positioning of licensed origins. In light of this, we discuss the complex and disparate phenotypes observed in mouse models and humans patients that arise due to defects in replication licensing proteins

DDK:The Outsourced Kinase of Chromosome Maintenance

SIMPLE SUMMARY: To ensure the maintenance of genetic stability prior to cell division a cell’s complement of chromosomes must be duplicated. This requires not only the replication of the chromosomal DNA but also the re-establishment the chromatin environment following duplication. To ensure the equal segregation of the genetic material to progeny cells, the duplicated chromatid pairs must remain physically coupled until cell division. The regulation of chromosome duplication is under the overall control of the cyclin-dependent kinases (CDK). In addition to maintaining global control of chromosome duplication, CDK directs the activation of a second kinase, the Dbf4-dependent kinase (DDK), which functions locally to facilitate the activation DNA replication and to coordinate this with the re-establishment of chromatin and the physical coupling of the chromatids following duplication. In this review, we discuss this ‘outsourcing’ by CDK to DDK of the activities that must be coordinated to ensure chromosome maintenance during cell division. ABSTRACT: The maintenance of genomic stability during the mitotic cell-cycle not only demands that the DNA is duplicated and repaired with high fidelity, but that following DNA replication the chromatin composition is perpetuated and that the duplicated chromatids remain tethered until their anaphase segregation. The coordination of these processes during S phase is achieved by both cyclin-dependent kinase, CDK, and Dbf4-dependent kinase, DDK. CDK orchestrates the activation of DDK at the G1-to-S transition, acting as the ‘global’ regulator of S phase and cell-cycle progression, whilst ‘local’ control of the initiation of DNA replication and repair and their coordination with the re-formation of local chromatin environments and the establishment of chromatid cohesion are delegated to DDK. Here, we discuss the regulation and the multiple roles of DDK in ensuring chromosome maintenance. Regulation of replication initiation by DDK has long been known to involve phosphorylation of MCM2-7 subunits, but more recent results have indicated that Treslin:MTBP might also be important substrates. Molecular mechanisms by which DDK regulates replisome stability and replicated chromatid cohesion are less well understood, though important new insights have been reported recently. We discuss how the ‘outsourcing’ of activities required for chromosome maintenance to DDK allows CDK to maintain outright control of S phase progression and the cell-cycle phase transitions whilst permitting ongoing chromatin replication and cohesion establishment to be completed and achieved faithfully

Both Chromosome Decondensation and Condensation Are Dependent on DNA Replication in C.elegans Embryos

SummaryDuring cell division, chromatin alternates between a condensed state to facilitate chromosome segregation and a decondensed form when DNA replicates. In most tissues, S phase and mitosis are separated by defined G1 and G2 gap phases, but early embryogenesis involves rapid oscillations between replication and mitosis. Using Caenorhabditis elegans embryos as a model system, we show that chromosome condensation and condensin II concentration on chromosomal axes require replicated DNA. In addition, we found that, during late telophase, replication initiates on condensed chromosomes and promotes the rapid decondensation of the chromatin. Upon replication initiation, the CDC-45-MCM-GINS (CMG) DNA helicase drives the release of condensin I complexes from chromatin and the activation or displacement of inactive MCM-2–7 complexes, which together with the nucleoporin MEL-28/ELYS tethers condensed chromatin to the nuclear envelope, thereby promoting chromatin decondensation. Our results show how, in an early embryo, the chromosome-condensation cycle is functionally linked with DNA replication

Improved design of all-optical processor for modular arithmetic

A new improved design of an all-optical processor that performs modular arithmetic is presented. The modulo-processor is based on all-optical circuit of interconnected semiconductor optical amplifier logic gates. The design allows processing times of less than 1 µs for 16-bit operation at 10 Gb/s and up to 32-bit operation at 100 Gb/s

Characterization of a multiresonance ring resonator-based optical device

We describe the linear and nonlinear transfer characteristics of a multi-resonance optical device consisting of two ring resonators coupled one to another and to a waveguide. The propagation effects displayed by the device are compared with those of a sequence of a waveguide-coupled fundamental ring resonators

Reconstitution of licensed replication origins on Xenopus sperm nuclei using purified proteins

BACKGROUND: In order to ensure precise chromosome duplication, eukaryotes "license" their replication origins during late mitosis and early G1 by assembling complexes of Mcm2-7 onto them. Mcm2-7 are essential for DNA replication, but are displaced from origins as they initiate, thus ensuring that no origin fires more than once in a single cell cycle. RESULTS: Here we show that a combination of purified nucleoplasmin, the origin recognition complex (ORC), Cdc6, RLF-B/Cdt1 and Mcm2-7 can promote functional origin licensing and the assembly of Mcm2-7 onto Xenopus sperm nuclei. The reconstituted reaction is inhibited by geminin, a specific RLF-B/Cdt1 inhibitor. Interestingly, the purified ORC used in the reconstitution had apparently lost the Orc6 subunit, suggesting that Orc6 is not essential for replication licensing. We use the reconstituted system to make a preliminary analysis of the different events occuring during origin assembly, and examine their nucleotide requirements. We show that the loading of Xenopus ORC onto chromatin is strongly stimulated by both ADP, ATP and ATP-γ-S whilst the loading of Cdc6 and Cdt1 is stimulated only by ATP or ATP-γ-S. CONCLUSIONS: Nucleoplasmin, ORC, Cdc6, RLF-B/Cdt1 and Mcm2-7 are the only proteins required for functional licensing and the loading of Mcm2-7 onto chromatin. The requirement for nucleoplasmin probably only reflects a requirement to decondense sperm chromatin before ORC can bind to it. Use of this reconstituted system should allow a full biochemical analysis of origin licensing and Mcm2-7 loading