Structure of the active form of human origin recognition complex and its ATPase motor module

Abstract: Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations. Full article

Researchers Assemble Five New Synthetic Yeast Chromosomes

A global research team has built five new synthetic yeast chromosomes, meaning that 30 percent of a key organism’s genetic material has now been swapped out for engineered replacements. This is one of several findings of a package of seven papers published March 10 as the cover story for Science.

Led by NYU Langone geneticist Jef Boeke, PhD, and a team of more than 200 authors, the publications are the latest from the Synthetic Yeast Project (Sc2.0). By the end of this year, this international consortium hopes to have designed and built synthetic versions of all 16 chromosomes—the structures that contain DNA—for the one-celled microorganism Baker’s yeast, known as S. cerevisiae.

Like computer programmers, scientists add swaths of synthetic DNA to—or remove stretches from—human, plant, bacterial, or yeast chromosomes in hopes of averting disease, manufacturing medicines, or making food more nutritious. Baker’s yeast have long served as an important research model because their cells share many features with human cells, but are simpler and easier to study. Rest

Scientists create first stable semisynthetic organism

Scientists at The Scripps Research Institute (TSRI) have announced the development of the first stable semisynthetic organism. Building on their 2014 study in which they synthesized a DNA base pair, the researchers created a new bacterium that uses the four natural bases (called A, T, C and G), which every living organism possesses, but that also holds as a pair two synthetic bases called X and Y in its genetic code.

TSRI Professor Floyd Romesberg and his colleagues have now shown that their can hold on indefinitely to the synthetic base pair as it divides. Their research was published January 23, 2017, online ahead of print in the journal Proceedings of the National Academy of Sciences. Rest

Listening in on Bug-Gut Chatter

Now, for the first time, scientists from Harvard Medical School have managed to “listen in” on the crosstalk between individual microbes and the entire cast of immune cells and genes expressed in the gut.

The experiments, published Feb. 16 in Cell, provide a blueprint for identifying important microbial influencers of disease and health and can help scientists develop precision-targeted treatments.

Past research has looked at links between disease and the presence or absence of certain classes of bacteria in the gut. By contrast, the HMS team homed in on one microbe at a time and its effects on nearly all immune cells and intestinal genes, an approach that offers a more precise understanding of the interplay between individual gut microbes and their hosts. Beyond that, the team said, the approach could help scientists screen for molecules or bacterial strains that can be used therapeutically to fine-tune certain immune responses.

“We set out to map out interactions between bacteria and the immune system in the hope that this could eventually lead to the development of an apothecary of agents tailored to modulate the immune system selectively and precisely,” said senior investigator Dennis Kasper, professor of medicine and microbiology and immunobiology at HMS. Rest

A Herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression

Abstract: Natural Killer (NK) cells are essential for control of viral infection and cancer. NK cells express NKG2D, an activating receptor that directly recognizes NKG2D ligands. These are expressed at low level on healthy cells, but are induced by stresses like infection and transformation. The physiological events that drive NKG2D ligand expression during infection are still poorly understood. We observed that the mouse cytomegalovirus encoded protein m18 is necessary and sufficient to drive expression of the RAE-1 family of NKG2D ligands. We demonstrate that RAE-1 is transcriptionally repressed by histone deacetylase inhibitor 3 (HDAC3) in healthy cells, and m18 relieves this repression by directly interacting with Casein Kinase II and preventing it from activating HDAC3. Accordingly, we found that HDAC inhibiting proteins from human herpesviruses induce human NKG2D ligand ULBP-1. Thus our findings indicate that virally mediated HDAC inhibition can act as a signal for the host to activate NK-cell recognition. DOI: 10.7554/eLife.14749.001

http://derisilab.ucsf.edu/pdfs/e14749-download.pdf

Pancreatic cancer biomarker bolsters nanoparticle-based diagnostic

Arizona State University’s Ye (Tony) Hu and his colleagues have delivered what they hope will be a double dose of good news for detecting pancreatic cancer. Pancreatic cancer is one of the leading causes of cancer deaths because it often goes undetected in early stages, according to the Mayo Clinic.

The researchers report a rapid and inexpensive nanoparticle-based diagnostic fueled, in part, by their second finding, a biomarker on the surface of vesicles released by pancreatic tumors (Nat. Biomed. Eng. 2017, DOI: 10.1038/s41551-016-0021).  Rest

DNA nanotubes self-assemble into molecular bridges between cells

In a microscopic feat that resembled a high-wire circus act, Johns Hopkins researchers have coaxed DNA nanotubes to assemble themselves into bridge-like structures arched between two molecular landmarks on the surface of a lab dish. This self-assembling bridge process, which may someday be used to connect electronic medical devices to living cells, was reported by the team recently in the journal Nature Nanotechnology. Rest

Noble Prize for Ben Feringa

The University of Groningen (a university I had the pleasure of visiting several years ago) news article. An excerpt below:

Feringa is internationally recognized as a pioneer in the field of molecular engines, as the many citations in a background article on nano engines in Nature confirm. One of the potential applications of his engines is the delivery of medication inside the human body. Besides molecular engines, Feringa is also involved in catalysis and smart medication that can, for instance, be turned on and off by light.”

Researchers develop DNA-based single-electron electronic devices

Nature has inspired generations of people, offering a plethora of different materials for innovations. One such material is the molecule of the heritage, or DNA, thanks to its unique self-assembling properties. Researchers at the Nanoscience Center (NSC) of the University of Jyväskylä and BioMediTech (BMT) of the University of Tampere have now demonstrated a method to fabricate electronic devices by using DNA. The DNA itself has no part in the electrical function, but acts as a scaffold for forming a linear, pearl-necklace-like nanostructure consisting of three gold nanoparticles. …

Gold nanoparticles are attached directly within the aqueous solution onto a DNA structure designed and previously tested by the involved groups. The whole process is based on DNA self-assembly, and yields countless of structures within a single patch. Ready structures are further trapped for measurements by electric fields.  Rest

Rebuilding the Building Blocks of Life

Rather than redesigning naturally occurring sequences, researchers employing protein de novo design use peptides that assemble and fold into protein-like structures, relying on two self-assembly principles: The first is peptide-based [1] and incorporates a coiled coil where the resulting folding profile is much easier to predict, helping scientists overcome a common headache in protein design.

The second principle utilizes oligonucleotides (ON),which are widely used in nanotechnology to generate higher-level structures [2], for example in DNA origami. What would happen if researchers combined both principles in the same design? In a new proof-of-concept paper recently published in Nature Communications, Wengel’s team answered this question while designing a novel class of artificial proteins [3]. Rest