Structural Maintenance of Chromosome (SMC) Proteins Link Microtubule Stability to Genome Integrity

Structural maintenance of chromosome (SMC) proteins are key organizers of chromosome architecture and are essential for genome integrity. They act by binding to chromatin and connecting distinct parts of chromosomes together. Interestingly, their potential role in providing connections between chromatin and the mitotic spindle has not been explored. Here, we show that yeast SMC proteins bind directly to microtubules and can provide a functional link between microtubules and DNA. We mapped the microtubule-binding region of Smc5 and generated a mutant with impaired microtubule binding activity. This mutant is viable in yeast but exhibited a cold-specific conditional lethality associated with mitotic arrest, aberrant spindle structures, and chromosome segregation defects. In an in vitro reconstitution assay, this Smc5 mutant also showed a compromised ability to protect microtubules from cold-induced depolymerization. Collectively, these findings demonstrate that SMC proteins can bind to and stabilize microtubules and that SMC-microtubule interactions are essential to establish a robust system to maintain genome integrity.     

Local genes for local bacteria: Evidence of allopatry in the genomes of transatlantic Campylobacter populations

The genetic structure of bacterial populations can be related to geographical locations of isolation. In some species, there is a strong correlation between geographical distance and genetic distance, which can be caused by different evolutionary mechanisms. Patterns of ancient admixture in Helicobacter pylori can be reconstructed in concordance with past human migration, whereas in Mycobacterium tuberculosis it is the lack of recombination that causes allopatric clusters. In Campylobacter, analyses of genomic data and molecular typing have been successful in determining the reservoir host species, but not geographical origin. We investigated biogeographical variation in highly recombining genes to determine the extent of clustering between genomes from geographically distinct Campylobacter populations. Whole‐genome sequences from 294 Campylobacter isolates from North America and the UK were analysed. Isolates from within the same country shared more recently recombined DNA than isolates from different countries. Using 15 UK/American closely matched pairs of isolates that shared ancestors, we identify regions that have frequently and recently recombined to test their correlation with geographical origin. The seven genes that demonstrated the greatest clustering by geography were used in an attribution model to infer geographical origin which was tested using a further 383 UK clinical isolates to detect signatures of recent foreign travel. Patient records indicated that in 46 cases, travel abroad had occurred <2 weeks prior to sampling, and genomic analysis identified that 34 (74%) of these isolates were of a non‐UK origin. Identification of biogeographical markers in Campylobacter genomes will contribute to improved source attribution of clinical Campylobacter infection and inform intervention strategies to reduce campylobacteriosis.     

Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions

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Inhibitors of myosin light chain kinase and phosphodiesterase reduce ventilator-induced lung injury.

Alveolar overdistension due to high peak inflation pressures (PIP) is associated with an increased capillary filtration coefficient (K(fc)). To determine which signal pathways contribute to this injury, we perfused isolated rat lungs with 5% bovine albumin in Krebs solution and measured K(fc) after successive 30-min periods of ventilation with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH(2)O. In a high-PIP control group, K(fc) increased significantly after ventilation with 30 and 35 cmH(2)O PIP, but significant increases were prevented by treatment with 100 microM trifluoperazine, an inhibitor of Ca(2+)/calmodulin, 500 nM ML-7, an inhibitor of myosin light chain kinase (MLCK), a combination of isoproterenol (20 microM) and rolipram (10 microM) to enhance intracellular cAMP levels, and a dose of KT-5720 (2 microM), which inhibits MLCK and protein kinase C. These studies suggest that the Ca(2+)/calmodulin-MLCK pathway augments capillary fluid leak after a modest high-PIP injury and that this is attenuated by kinase inhibition and increased intracellular cAMP.