Tag: DNA

Brookhaven’s Top 10 Discoveries of 2024

Brookhaven’s Top 10 Discoveries of 2024

Lab celebrates a year of scientific successes, from creating the biggest bits of antimatter to improving qubits, catalysts, batteries, and more!

UPTON, N.Y. — With one-of-a-kind research facilities leveraged by scientists from across the nation and around the world, the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory is a veritable city of science. Each year brings discoveries, from the scale of subatomic particles to the vastness of Earth’s atmosphere and the cosmos, that have the potential to power new technologies and provide solutions to major societal challenges. Here, the Lab presents, in no particular order, its top 10 discoveries of 2024 … plus a few major Brookhaven Lab milestones.

Heaviest antimatter nucleus

Antimatter sounds exotic, but it really does exist — just not for long. This year, scientists studying collisions of atomic nuclei at the Relativistic Heavy Ion Collider (RHIC) — an “atom smasher” that recreates the conditions of the early universe — discovered the heaviest antimatter nucleus ever detected. It’s composed of four antimatter particles: an antiproton, two antineutrons, and a particle called an antihyperon. It lasts only a fraction of a second before decaying into other particles. To find it, physicists from RHIC’s STAR collaboration searched through particles streaming from billions of collisions to find just 16 of the rare “antihyperhydrogen-4” particles. There used to be lots of antimatter, back when the universe first formed, but when antimatter meets ordinary matter, the two self-destruct. The ability to create new antimatter particles today, like these heavy antimatter nuclei, gives scientists new ways to test for matter-antimatter differences that might explain why the universe is made only of matter. 

Low-temp, direct conversion of natural gas to liquid fuel

Brookhaven Lab chemists engineered a highly selective catalyst that can convert methane, a major component of natural gas, into methanol, an easily transportable liquid fuel, in a single, one-step reaction. This direct process for methane-to-methanol conversion runs at a temperature lower than required to make tea and exclusively produces methanol without additional byproducts. That’s a big advance over more complex traditional conversions that typically require three separate reactions, each under different conditions, including vastly higher temperatures. The simplicity of the system could make it particularly useful for tapping “stranded” natural gas reserves in isolated rural areas, far from the costly infrastructure of pipelines and chemical refineries, and without the need to transport high-pressure, flammable liquified natural gas. The team made use of tools at two DOE Office of Science user facilities at Brookhaven Lab, the Center for Functional Nanomaterials and the National Synchrotron Light Source II. They are exploring ways to work with entrepreneurial partners to bring the technology to market.

Plants’ sugar-sensing machinery

Proteins are molecular machines, with flexible pieces and moving parts. Understanding how these parts move helps scientists unravel the function that a protein plays in living things — and potentially how to change its effects. This year, a team led by Brookhaven Lab biochemists working with colleagues from DOE’s Pacific Northwest National Laboratory discovered how protein machinery in plants controls whether the plants can grow and make energy-intensive products such as oil — or instead put in place a series of steps to conserve precious resources. The researchers showed how the molecular machinery is regulated by a molecule that rises and falls with the level of sugar, the product of photosynthesis and plants’ main energy source. The research could help identify proteins or parts of proteins that scientists could engineer to make plants that produce more oil for use as biofuels or other oil-based products.

Protecting a promising qubit material

Tantalum is a superconducting material that shows great promise for building qubits, the basis of quantum computers. This year, a team that spans multiple Brookhaven departments discovered that adding a thin layer of magnesium improves tantalum by keeping it from oxidizing. The coating also improves tantalum’s purity and raises the temperature at which it operates as a superconductor. All three effects may increase tantalum’s ability to hold onto quantum information in qubits. This work was carried out as part of the Co-design Center for Quantum Advantage, a Brookhaven-led National Quantum Information Science Research Center, and included scientists from the Lab’s Condensed Matter Physics & Materials Science Department, Center for Functional Nanomaterials, and National Synchrotron Light Source II, as well as theorists at DOE’s Pacific Northwest National Laboratory. It built on earlier work that also included scientists from Princeton University.

Read more on BNL website

Newly discovered protein stops DNA damage

Newly discovered protein stops DNA damage

Researchers from Western University have discovered a protein that has the never-before-seen ability to stop DNA damage in its tracks. The finding could provide the foundation for developing everything from vaccines against cancer, to crops that can withstand the increasingly harsh growing conditions brought on by climate change.

The researchers found the protein – called DdrC (for DNA Damage Repair Protein C) — in a fairly common bacterium called Deinococcus radiodurans (D. radiodurans), which has the decidedly uncommon ability to survive conditions that damage DNA – for example, 5,000 to 10,000 times the radiation that would kill a regular human cell. Lead researcher Robert Szabla says Deinococcus also excels in repairing DNA that has already been damaged.“It’s as if you had a player in the NFL who plays every game without a helmet or pads,” says Szabla, a grad student in Western’s Department of Biochemistry. “He’d end up with a concussion and multiple broken bones every single game, but then miraculously make a full recovery overnight in time for practice the next day.” He and his colleagues discovered that DdrC is a key player in this repair process.

Read more on CLS website

Repairing genetic damage with sunlight

Repairing genetic damage with sunlight

DNA damage to the genetic material DNA drives cancer, ageing, and cell death. Therefore, DNA repair is crucial for all organisms, and a deeper understanding of this basic function helps us better comprehend how life around us survives and thrives. An international team of researchers has now revealed how the enzyme photolyase efficiently channels the energy of sunlight into DNA repair chemistry.

All life under the sun must cope with harmful UV rays. UV damage can take many forms, but DNA, the molecule that carries the genetic information of all living organisms, is especially vulnerable. For instance, UV can drive chemical cross-linking reactions of DNA, potentially introducing errors into the genetic code. This cross-linking can lead to cell death or – in the worst cases – mutagenesis and cancer. Such damage is not uncommon; under bright sunlight, a human skin cell can undergo 50-100 cross linking reactions per second.

“To survive, life has evolved powerful DNA repair mechanisms. One especially elegant solution is provided by the enzyme photolyase,” explains DESY scientist Thomas J. Lane, who is also a researcher in the Cluster of Excellence “CUI: Advanced Imaging of Matter” at Universität Hamburg. The enzyme uses sunlight to repair damage caused by sunlight. Photolyase is able to recognize the location where UV irradiation has cross-linked DNA and grabs onto those bits of damaged DNA. Then, it can capture a blue photon from the sun, and use it to perform repair chemistry, turning the DNA back into its original, healthy form.

To better understand how photolyase works, the scientists were particularly interested first in the form of the enzyme immediately after absorbing a photon, but before repairing the DNA. Second, they wanted to find out the exact sequence of bond-breaking chemical reactions necessary to turn damaged DNA into healthy DNA. As a third step, the team sought to better understand how photolyase can specifically recognize which DNA is damaged.

Conducting time-resolved crystallography at the SwissFEL X-ray free-electron laser of PSI the scientists were able to capture the excited state of the photolyase chromophore, letting them understand how the enzyme efficiently channels the energy of sunlight into DNA repair chemistry. “This research was only made possible by the recent development of X-ray free-electron laser sources. Their intense femtosecond-duration pulses let us record flash X-ray photographs that freeze all atomic motion so that we can follow the reaction step by step at the speed of molecules,” says first author Nina-Eleni Christou from DESY.

Read more on PSI website

Image: PSI researcher Camila Bacellar is pleased about the success in precisely analysing the DNA repair enzyme photolyase at the Alvra beamline of the Swiss X-ray free-electron laser SwissFEL.

Credit: Paul Scherrer Institute/Markus Fischer

A closer look at how cells package DNA

A closer look at how cells package DNA

Cryo-imaging reveals how cells efficiently store the genome

Our cells use an ensemble of histone proteins to fold and package the DNA genome into the nucleus. Histones also determine whether to expose DNA to enzymes to allow processes like gene expression, replication, and repair to occur. Although many in vitro studies have explored the mechanism histones use to fold and package DNA into higher-order structures called chromatin, less is known about chromatin organisation inside the nucleus of intact cells, and understanding this phenomenon could be key to understanding multiple DNA-associated processes. Recent advances in cryo-electron tomography have enabled scientists to observe these structures within the nucleus of rapidly cryopreserved cells. Reporting in Nature Communications, scientists at the University of Oxford collaborated with the electron Bio-Imaging Centre (eBIC) at the Diamond Light Source to capture chromatin in the nucleus of immune T cells, revealing that DNA is folded into more flexible and heterogenous fibres than previously modelled. Their experiments lay the groundwork for future studies into the roles of chromatin in health and disease.

Packing the essentials

Have you ever rushed to pack clothes into a suitcase and skipped the folding step only to find the suitcase wouldn’t close? Though it may have been a struggle, it doesn’t compare to the challenge our cells face when they pack 2 metres of DNA into a nucleus 200,000 times smaller in width. Here an efficient folding mechanism is key, and histone proteins direct the operation.

A complex of histone proteins act as a spool around which 147 base pairs of DNA can wind like thread. Multiple histone spools called nucleosomes can be found along the length of a DNA molecule and coil its strands into so-called chromatin. When chromatin is purified and observed using electron microscopy, scientists have observed that nucleosomes are spaced apart at regular intervals like beads on a string. These beads can then cluster together to form thicker chromatin fibres that pack the DNA into an even smaller volume.

Beyond efficiently folding DNA to fit inside the nucleus, histones play vital roles in regulating gene expression, DNA replication, and repair by loosening or tightening their grip on DNA and controlling its exposure to enzymes. An in-depth understanding of the folding mechanism could help researchers understand how chromatin affects multiple processes within the nucleus.

Read more on the Diamond website

Organic matter found in 44-million-year-old beetle fossil

Organic matter found in 44-million-year-old beetle fossil

Remember Jurassic Park? The dinosaurs in that movie franchise were brought to life through DNA found in amber. The DNA purportedly came from mosquitoes that had taken blood from dinosaurs prior to being trapped in the tree resin that turned into amber.

Amber, a semi-precious stone that is fossilized tree resin, often contains the fossilized remains of insects and other small creatures, with little, if any, organic matter left. No organic matter, no dinosaur DNA, no Jurassic Park.

However, a team of researchers from the University of Regina, Royal Saskatchewan Museum, and Institute of Life Sciences and Technologies at Daugavpils University in Latvia, have now identified what appears to be organic matter in a 44-million-year-old beetle fossilized in amber.

This remarkable finding, and the methodology used in making it, has been published in Nature’s Scientific Reports, the fifth most-cited journal in the world.

“Using a set of advanced techniques we’ve not tried before, we took a 44-million-year-old beetle trapped in Baltic amber to see if it was possible that any preserved organic material might be present,” says U of R master’s of science student Jerit Mitchell, lead author of the study.

Dr. Mauricio Barbi, a U of R physics professor, says the team used the synchrotron radiation facilities at the University of Saskatchewan’s Canadian Light Source (CLS) in Saskatoon to extract high-resolution 3D micro-computed tomography (micro-CT) images of the beetle.

“The synchrotron mid-infrared radiation gave us the capability to identify possible organic compounds in the specimen. We then complemented these two synchrotron radiation techniques by using a scanning electron microscope to provide further high-resolution images of the beetle and to determine the specific chemical elements present in the sample,” says Barbi, who led the team that discovered structurally preserved fossilized dinosaur cell layers in the skin of a 72-million-year-old hadrosaur.”

Read more on the website

Image: Jerit Mitchell gazing at a millions-year-old fossilized beetle

 Credit: U of R Photography

Targeting a parasite’s DNA could be more effective way to treat malaria

Targeting a parasite’s DNA could be more effective way to treat malaria

Research from the University of Sheffield using Diamond has explored a new way of killing the Plasmodium parasite that causes malaria. 

According to the World Health Organisation, there were 241 million cases of malaria and 627,000 deaths worldwide in 2020 – making the study and treatment of this disease a high-priority issue for scientists around the world. In a feasibility study, researchers from the University of Sheffield used Diamond to reveal a novel way of fighting the life-threatening disease, malaria. The study discovered molecules that interfered with the parasite’s DNA processing enzyme, but not the equivalent human one. 

A research team from the University of Sheffield’s Department of Infection, Immunity and Cardiovascular Disease examined and targeted an enzyme that maintains the classic double-helical structure of the malaria parasite’s DNA, which contains the blueprint of life, which could be a more effective way to combat malaria.

Read more on the Diamond website

Image: A flap endonuclease cuts DNA (the orange intertwined worms), credit University of Sheffield

Searching for the chemistry of life

Searching for the chemistry of life

Study shows possible new way to create DNA base pairs

In the search for the chemical origins of life, researchers have found a possible alternative path for the emergence of the characteristic DNA pattern: According to the experiments, the characteristic DNA base pairs can form by dry heating, without water or other solvents. The team led by Ivan Halasz from the Ruđer Bošković Institute and Ernest Meštrović from the pharmaceutical company Xellia presents its observations from DESY’s X-ray source PETRA III in the journal Chemical Communications.

“One of the most intriguing questions in the search for the origin of life is how the chemical selection occurred and how the first biomolecules formed,” says Tomislav Stolar from the Ruđer Bošković Institute in Zagreb, the first author on the paper. While living cells control the production of biomolecules with their sophisticated machinery, the first molecular and supramolecular building blocks of life were likely created by pure chemistry and without enzyme catalysis. For their study, the scientists investigated the formation of nucleobase pairs that act as molecular recognition units in the Deoxyribonucleic Acid (DNA).

Read more on the PETRA III (DESY) website

Image: From the mixture of all four nucleobases, A:T pairs emerged at about 100 degrees Celsius and G:C pairs formed at 200 degrees Celsius. Credit: Ruđer Bošković Institute, Ivan Halasz

First structure of a DNA crosslink repair ligase determined

First structure of a DNA crosslink repair ligase determined

Diamond’s Electron Bio-Imaging Facility (eBIC) has been used to generate the first 3D structure of the Fanconi anaemia (FA) core complex, a multi-subunit E3 ubiquitin ligase required for the repair of damaged DNA. The work, led by Dr Lori Passmore from the MRC Laboratory of Molecular Biology and a team of researchers, has been published today in Nature, and their research provides the molecular architecture of the FA core complex and new insights into how the complex functions.

The FA pathway senses and repairs DNA crosslinks that occur after exposure to chemicals including chemotherapeutic agents and alcohol, but also as a result of normal cellular metabolism. The megadalton FA core complex acts as an E3 ubiquitin ligase to initiate removal of these DNA crosslinks, helping to repair the damage caused. The research team used eBIC’s imaging facilities to make a major breakthrough in understanding the FA core complex by determining its structure using an integrative approach including cryo-electron microscopy and mass spectrometry.

Dr Peijun Zhang, Director of eBIC notes that:

Enabling cutting-edge research like this is exactly why we established eBIC, to provide scientists with state-of-the-art experimental equipment and expertise in the field of cryo-electron microscopy, for both single particle analysis and cryo-electron tomography. Determining the structure of the FA core complex for the first time is a fantastic achievement for the MRC research team.

>Read more on the Diamond Light Source website

Image: The FA core complex.
Credit: Phospho Biomedical Animation

Mechanism of thiopurine resistance in acute lymphoblastic leukemia

Mechanism of thiopurine resistance in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is an aggressive lymphoid malignancy that is currently the leading cause of cancer in pediatric patients1. Despite intensified chemotherapy regimens, the cure rates of ALL only approaches 40%2. Specific mutations in the cytosolic 5’-nucleotidase II (NT5C2) gene are present in about 20% of relapsed pediatric T-ALL and 3-10% of relapsed B-precursor ALL cases3,4.

NT5C2 is a cytosolic nucleotidase that maintains intracellular nucleotide pool levels by exporting excess purine nucleotides out of the cell5.  NT5C2 can also dephosphorylate and inactivate the metabolites of the 6-thioguanine (6-TG) and 6-mercaptopurine (6-MP) commonly used to treat ALL6. Thus, relapse associated activating mutations in NT5C2 confer resistance to 6-MP and 6-TG chemotherapy. Upon allosteric activation, a disordered region of NT5C2 adopts a helical configuration (helix A) and facilitates substrate binding and catalysis (Fig. 1a)7.  Mutations in this regulatory region of NT5C2 have been modeled to strongly activate NT5C2.  However, the majority of NT5C2 mutations associated with relapsed ALL do not occur in this region.
To better understand the mechanisms by which these gain-of function NT5C2 mutations lead to increased nucleotidase activity, Dieck, Tzoneva, Forouhar and colleagues investigated additional regulatory elements that may control NT5C2 activation.  They collected crystallographic data for several mutant NT5C2 homotetramers at SSRL (NT5C2-537X D52N/D407A in active state (BL9-2), NT5C2-Q523X D52N in basal state and in active state (BL14-1) and full-length NT5C2 R39Q/D52N in basal state (BL12-2)) and used the structural information as a guide in the understanding of the mechanistic details.

>Read more on the Stanford Synchrotron Radiation Lightsource website

Figure (a) A ribbon diagram of the active structure of NT5C2 WT, in which the allosteric helix A (αA) is shown in dark purple. The N and C termini amino acids (S4 and S488), and the termini amino acids (L402 and R421) of the disordered region in the arm segment are also labeled. Panels b and c shows ribbon and surface (for subunit B) depictions of basal (b) and active dimers (c) of WT.

New forensic DNA profiling technique on the horizon

New forensic DNA profiling technique on the horizon

A study recently conducted at the Circular Dichroism beamline (B23) here at Diamond Light Source could pave the way to a new forensic DNA profiling technique. Researchers hailing from the Ivanovo State University of Chemistry and Technology, Russia, The University of Southampton and Diamond investigated the application of specially designed DNA building blocks.

DNA is a versatile template that can be used for a variety of applications. It is made up of building blocks known as nucleotides (labelled A, C, G and T) which form long strands that bind to complementary sequences and give the familiar double helix. The nucleotides can be tailor made to build new functional molecules for biotechnology, analytics, or even materials science.

>Read more on the Diamond Light Source website

 

Structural Mechanisms of Histone Recognition by Histone Chaperones

Structural Mechanisms of Histone Recognition by Histone Chaperones

Chromatin is the complex of DNA and proteins that comprises the physiological form of the genome. Non-covalent interactions between DNA and histone proteins are necessary to compact large eukaryotic genomes into relatively small cell nuclei. The nucleosome is the fundamental repeating unit of chromatin, and is composed of 147bp of DNA wrapped around an octamer of histone proteins: 2 copies of each H2A, H2B, H3 and H4.

Assembly of nucleosomes in the cell requires the coordinated effort of many proteins including ATP-dependent chromatin remodeling enzymes and ATP-independent histone chaperone proteins. Histone chaperones are a large class of proteins responsible for binding the highly basic histone proteins, shielding them from non-specific interactions, facilitating nuclear import of histones, and finally depositing histones onto DNA to form nucleosomes. Despite performing many overlapping functions, histone chaperone proteins are highly structurally divergent. However, nearly all histone chaperones contain highly charged intrinsically disordered regions (IDRs)1. In many cases truncation of these conserved regions results in loss of histone affinity and deposition functions.

>Read more on the Stanford Synchrotron Radiation Lightsource

Image: (extract) SAXS analysis of Npm Core+A2 truncation (1-145) bound to five H2A/H2B dimers. Left: small angle x-ray scattering curve of the complex (purple dots). Simulated SAXS curve from the best scoring structural model shown as a black line. Right: SAXS envelope of the complex (pink) with the best scoring structural model inside. Positioning of H2A/H2B dimers by NMR and SAXS structural restraints. Full image here.

Molecular Movie

Molecular Movie

Researchers Create Molecular Movie of Virus Preparing to Infect Healthy Cells

With SLAC’s X-ray laser, scientists captured a virus changing shape and rearranging its genome to invade a cell.

A research team has created for the first time a movie with nanoscale resolution of the three-dimensional changes a virus undergoes as it prepares to infect a healthy cell. The scientists analyzed thousands of individual snapshots from intense X-ray flashes, capturing the process in an experiment at the Department of Energy’s SLAC National Accelerator Laboratory.

>Read More