New Drug Inhibits the Growth of Cancer Cells (Medicine)

Blocking gene expression in mitochondria in mice stops cancer cells from growing.

A newly developed compound starves cancer cells by attacking their “power plants” – the so-called mitochondria. The new compound prevents the genetic information within mitochondria from being read. Researchers from the Max Planck Institute for Biology of Ageing in Cologne, the Karolinska Institute in Stockholm and the University of Gothenburg report in their study that this compound could be used as a potential anti-tumour drug in the future; not only in mice but also in human patients.

Cartoon representation of the POLRMT-Inhibitor complex. © Hauke S. Hillen

Mitochondria provide our cells with energy and cellular building blocks necessary for normal tissue and organ function. For a long time, the growth of cancer cells was assumed to be independent of mitochondrial function. However, this long-standing dogma has been challenged in recent years. Especially cancer stem cells are highly dependent on mitochondrial metabolism. Due to the central role of mitochondria for normal tissue function, and because drugs that target mitochondrial functions are usually very toxic, it has so far proven difficult to target mitochondria for cancer treatment.

Now an international team of researchers has found a way to overcome these difficulties. “We managed to establish a potential cancer drug that targets mitochondrial function without severe side effects and without harming healthy cells”, explains Nina Bonekamp, one of the lead authors of the study. Mitochondria contain their own genetic material, the mitochondrial DNA molecules (mtDNA), whose gene expression is mediated by a dedicated set of proteins. One such protein is the enzyme “mitochondrial RNA polymerase”, abbreviated to POLRMT. “Previous findings of our group have shown that rapidly proliferating cells, such as embryonic cells, are very sensitive to inhibition of mtDNA expression, whereas differentiated tissues such as skeletal muscle can tolerate this condition for a surprisingly long time. We reasoned that POLRMT as a key regulator of mtDNA expression might provide a promising target”, says Nils-Göran Larsson, head of the research team.

Compound inhibits mitochondrial RNA polymerase

In collaboration with the Lead Discovery Center, a translational drug discovery organization established by Max Planck Innovation, the research team designed a high-throughput test method for identifying a chemical compound that inhibits POLRMT. The POLRMT inhibitor strongly decreased cancer cell viability and tumour growth in tumour-bearing mice, but was generally well tolerated by the animals. “Our data suggest that we basically starve cancer cells into dying without large toxic side effects, at least for a certain amount of time. This provides us with a potential window of opportunity for treatment of cancer”, says Nina Bonekamp. “Another advantage of our inhibitor is that we exactly know where it binds to POLRMT and what it does to the protein. This is in contrast to some other drugs that are even in clinical use.” With the help of ACUS Laboratories in Cologne and the Max Planck Institute for Biophysical Chemistry in Göttingen, the team identified the chemical binding site of the inhibitor and obtained structural information of the POLRMT-Inhibitor complex.

Bonekamp and Larsson agree that it has been an exciting journey to translate basic findings into a potential drug. They are all the more excited about the possibilities that their findings will open up. “Given the central role of mitochondrial metabolism within the cell, I am sure that our inhibitor of mitochondrial gene expression can be used as a tool in a variety of different areas”, explains Bonekamp. “Of course, it is intriguing to further pursue its potential as an anti-cancer drug, but also as a model compound to further understand the cellular effects of mitochondrial dysfunction and mitochondrial diseases.”

Reference: Nina A. Bonekamp, Bradley Peter, Hauke S. Hillen, Andrea Felser, Tim Bergbrede, Axel Choidas, Moritz Horn, Anke Unger, Raffaella di Lucrezia, Ilian Atanassov, Xinping Li, Uwe Koch, Sascha Menninger, Joanna Boros, Peter Habenberger, Patrick Giavalisco, Patrick Cramer, Martin S. Denzel, Peter Nussbaumer, Bert Klebl, Maria Falkenberg, Claes M. Gustafsson and Nils-Göran Larsson. “Equal first authors
Small molecule inhibitors of human mitochondrial DNA transcription”, Nature, 2020. https://www.nature.com/articles/s41586-020-03048-z

Provided by Max Planck Gesellschaft

Chemists Describe a New Form of Ice (Chemistry)

Scientists from the United States, China, and Russia have described the structure and properties of a novel hydrogen clathrate hydrate that forms at room temperature and relatively low pressure. Hydrogen hydrates are a potential solution for hydrogen storage and transportation, the most environmentally friendly fuel. The research was published in the journal Physical Review Letters.

A novel hydrogen clathrate hydrate © Pavel Odinev / Skoltech

Ice is a highly complex substance with multiple polymorphic modifications that keep growing in number as scientists make discoveries. The physical properties of ice vary greatly, too: for example, hydrogen bonds become symmetric at high pressures, making it impossible to distinguish a single water molecule, whereas low pressures cause proton disorder, placing water molecules in many possible spatial orientations within the crystal structure. The ice around us, including snowflakes, is always proton-disordered. Ice can incorporate xenon, chlorine, carbon dioxide, or methane molecules and form gas hydrates, which often have a different structure from pure ice. The vast bulk of Earth’s natural gas exists in the form of gas hydrates.

In their new study, chemists from the United States, China, and Russia focused on hydrogen hydrates. Gas hydrates hold great interest both for theoretical research and practical applications, such as hydrogen storage. If stored in its natural form, hydrogen poses an explosion hazard, whereas density is way too low even in compressed hydrogen. That is why scientists are looking for cost-effective hydrogen storage solutions.

“This is not the first time we turn to hydrogen hydrates. In our previous research, we predicted a novel hydrogen hydrate with 2 hydrogen molecules per water molecule. Unfortunately, this exceptional hydrate can only exist at pressures above 380,000 atmospheres, which is easy to achieve in the lab but is hardly usable in practical applications. Our new paper describes hydrates that contain less hydrogen but can exist at much lower pressures,” Skoltech professor Artem R. Oganov says.

The crystal structure of hydrogen hydrates strongly depends on pressure. At low pressures, it has large cavities which, according to Oganov, resemble Chinese lanterns, each accommodating hydrogen molecules. As pressure increases, the structure becomes denser, with more hydrogen molecules packed into the crystal structure, although their degrees of freedom become significantly fewer.

In their research published in the Physical Review Letters, the scientists from the Carnegie Institution of Washington (USA) and the Institute of Solid State Physics in Hefei (China) led by Alexander F. Goncharov, a Professor at these two institutions, performed experiments to study the properties of various hydrogen hydrates and discovered an unusual hydrate with 3 water molecules per hydrogen molecule. The team led by Professor Oganov used the USPEX evolutionary algorithm developed by Oganov and his students to puzzle out the compound’s structure responsible for its peculiar behavior. The researchers simulated the experiment’s conditions and found a new structure very similar to the known proton-ordered C1 hydrate but differing from C1 in water molecule orientations. The team showed that proton disorder should occur at room temperature, thus explaining the X-ray diffraction and Raman spectrum data obtained in the experiment.

Reference: Yu Wang, Konstantin Glazyrin, Valery Roizen, Artem R. Oganov, Ivan Chernyshov, Xiao Zhang, Eran Greenberg, Vitali B. Prakapenka, Xue Yang, Shu-qing Jiang, and Alexander F. Goncharov, “Novel Hydrogen Clathrate Hydrate”, Phys. Rev. Lett. 125, 255702 – Published 18 December 2020. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.125.255702

Provided by SKOLTECH

Fluvial Mapping of Mars (Planetary Science)

It took fifteen years of imaging and nearly three years of stitching the pieces together to create the largest image ever made, the 8-trillion-pixel mosaic of Mars’ surface. Now, the first study to utilize the image in its entirety provides unprecedented insight into the ancient river systems that once covered the expansive plains in the planet’s southern hemisphere. These three billion-year-old sedimentary rocks, like those in Earth’s geologic record, could prove valuable targets for future exploration of past climates and tectonics on Mars.

(A) A suite of ridges on Mars (at -67.64°E, 43.37°S). To determine whether features are ridges or valleys, the researchers rely on lighting in the impact craters (depressions). Based on the craters, the light is coming from the top of the image. Because the fluvial ridges are casting shadows to the south, they can infer that the feature is sticking up from the surface–a ridge rather than a valley. (B) A similar, “analogue” environment on Earth. Fluvial ridges similar to the ones on Mars are in California’s Amargosa river system, although with water still running through the system, it’s the active precursor to the ridges that are remnant on Mars. © Images courtesy J. Dickson.

The work, published this month in Geology, complements existing research into Mars’ hydrologic history by mapping ancient fluvial (river) ridges, which are essentially the inverse of a riverbed. “If you have a river channel, that’s the erosion part of a river. So, by definition, there aren’t any deposits there for you to study,” Jay Dickson, lead author on the paper, explains. “You have rivers eroding rocks, so where did those rocks go? These ridges are the other half of the puzzle.” Using the mosaic, as opposed to more localized imagery, let the researchers solve that puzzle on a global scale.

Mars used to be a wet world, as evidenced by rock records of lakes, rivers, and glaciers. The river ridges were formed between 4 and 3 billion years ago, when large, flat-lying rivers deposited sediments in their channels (rather than only having the water cut away at the surface). Similar systems today can be found in places like southern Utah and Death Valley in the U.S., and the Atacama Desert in Chile. Over time, sediment built up in the channels; once the water dried up, those ridges were all that was left of some rivers.

The ridges are present only in the southern hemisphere, where some of Mars’ oldest and most rugged terrain is, but this pattern is likely a preservation artifact. “These ridges probably used to be all over the entire planet, but subsequent processes have buried them or eroded them away,” Dickson says. “The northern hemisphere is very smooth because it’s been resurfaced, primarily by lava flows.” Additionally, the southern highlands are “some of the flattest surfaces in the solar system,” says Woodward Fischer, who was involved in this work. That exceptional flatness made for good sedimentary deposition, allowing the creation of the records being studied today.

Whether or not a region has fluvial ridges is a basic observation that wasn’t possible until this high-resolution image of the planet’s surface was assembled. Each of the 8 trillion pixels represents 5 to 6 square meters, and coverage is nearly 100 percent, thanks to the “spectacular engineering” of NASA’s context camera that has allowed it to operate continuously for well over a decade. An earlier attempt to map these ridges was published in 2007 by Rebecca Williams, a co-author on the new study, but that work was limited by imagery coverage and quality.

“The first inventory of fluvial ridges using meter-scale images was conducted on data acquired between 1997 and 2006,” Williams says. “These image strips sampled the planet and provided tantalizing snapshots of the surface, but there was lingering uncertainty about missing fluvial ridges in the data gaps.”

The resolution and coverage of Mars’ surface in the mosaic has eliminated much of the team’s uncertainty, filling in gaps and providing context for the features. The mosaic allows researchers to explore questions at global scales, rather than being limited to patchier, localized studies and extrapolating results to the whole hemisphere. Much previous research on Mars hydrology has been limited to craters or single systems, where both the sediment source and destination are known. That’s useful, but more context is better in order to really understand a planet’s environmental history and to be more certain in how an individual feature formed.

In addition to identifying 18 new fluvial ridges, using the mosaic image allowed the team to re-examine features that had previously been identified as fluvial ridges. Upon closer inspection, some weren’t formed by rivers after all, but rather lava flows or glaciers. “If you only see a small part of [a ridge], you might have an idea of how it formed,” Dickson says. “But then you see it in a larger context–like, oh, it’s the flank of a volcano, it’s a lava flow. So now we can more confidently determine which are fluvial ridges, versus ridges formed by other processes.”

Now that we have a global understanding of the distribution of ancient rivers on Mars, future explorations–whether by rover or by astronauts–could use these rock records to investigate what past climates and tectonics were like. “One of the biggest breakthroughs in the last twenty years is the recognition that Mars has a sedimentary record, which means we’re not limited to studying the planet today,” Fischer says. “We can ask questions about its history.” And in doing so, he says, we learn not only about a single planet’s past, but also find “truths about how planets evolved… and why the Earth is habitable.”

As this study is only the first to use the full mosaic, Dickson looks forward to seeing how it gets put to use next. “We expect to see more and more studies, similar in scale to what we’re doing here, by other researchers around the world,” he says. “We hope that this ‘maiden voyage’ scientific study sets an example for the scale of science that can be done with a product this big.”

Reference: J.L. Dickson; M.P. Lamb; R.M.E. Williams; A.T. Hayden; W.W. Fischer, “The global distribution of depositional rivers on early Mars”, Geology, 2020. https://doi.org/10.1130/G48457.1 https://pubs.geoscienceworld.org/gsa/geology/article-abstract/doi/10.1130/G48457.1/593435/The-global-distribution-of-depositional-rivers-on

Provided by Geological Society of America

Scientists Pinpoint Molecular Cause for Severe Disorder in Children (Biology)

A team of scientists from the University of Ottawa have opened a window into the cause of a rare genetic disorder that causes mortality in young children.

Damien D’Amours and his team at the Ottawa Institute of Systems Biology needed three years to discover the molecular defects associated with the LIC Syndrome, a serious genetic disorder that affects young children and result in acute respiratory distress, immune deficiency and abnormal chromosomes.

By modelling the mutations causing the LIC syndrome in the system, this showed that the mutations affect ability of the Smc5/6 complex to repair chromosomes in cells, thus explaining how LIC mutations affect the ability of cells to maintain healthy genomes. © D’Amours Lab/University of Ottawa

Onset of symptoms occurs in the first few months after birth in infants suffering from Lung disease Immunodeficiency and Chromosome breakage (LIC). Typically, patients experience failure to thrive and immune deficiency, which can eventually progress to fatal pediatric pulmonary disease in early childhood. The disease is caused by small inactivating mutations in NSMCE3, a gene encoding an essential factor found in the nucleus of human cells.

This research represents one of the most important milestones in developing treatments to improve the lives of LIC syndrome patients. Damien D’Amours is a Full Professor in the Department of Cellular & Molecular Medicine of the Faculty of Medicine whose lab is focused understanding the mechanisms used by cells to promote efficient cell division and proliferation.

He provided further insights into the study’s findings.

Damien D’Amours © University of Ottawa

What exactly have you discovered?

“We discovered how defects in a “DNA compaction machine” within our cells can cause a rare genetic disorder that kills young children (i.e., the LIC syndrome). We found the molecular cause by using an exciting mix of biophysics, advanced genetics and classical biochemistry to demonstrate that an enzyme has the rare ability to compact DNA within our cells.”

How did you do it?

“We developed a completely novel system to purify a human enzyme that nobody in the world has ever successfully purified – the “Smc5/6 complex.” The Smc5/6 complex is a crucial effector of chromosome integrity, and our breakthrough allowed us to reveal the structure of the enzyme and its powerful ability to compact DNA structure in space. We then modelled the mutations causing the LIC syndrome in our system and showed that the mutations affect ability of the Smc5/6 complex to repair chromosomes in cells, thus explaining how LIC mutations affect the ability of cells to maintain healthy genomes.”

You used the “systems biology” approach to reach your conclusions; please explain this.

“The advent of systems biology has revolutionized biomedical research in recent years. This approach relies on the use of integrative “omics” technologies and model organisms to provide a systems-level understanding of human diseases. (Omics is a general term to describe “large-scale genomics, proteomics, and metabolomics technologies.”) The University of Ottawa has been at the forefront of this revolution in research with the creation of the Ottawa Institute of Systems Biology (OISB). We took advantage of the systems biology approach to develop completely new systems to purify an enzyme never purified before. Then we used innovative mix of biophysics, proteomics and classical biochemistry to reveal the mode of action of the Smc5/6 complex and how mutations in this complex can cause severe defects in DNA repair.”

Why is this an important find?

“My research team and our collaborators are performing research at the absolute cutting-edge of our field and, as the leading laboratory on this project, we feel our research represents one of the most important milestones on the way to devise treatments for LIC syndrome patients. Prior to our work, nobody knew the biochemical cause for the LIC syndrome and how the enzyme mutated in this disease might affect the cells of patients/children; we provided answers to these fundamental questions.”

Provided by University of Ottawa

How Roundworms Decide The Time is Right? (Biology)

Transforming a fertilized egg into a fully functional adult is a complicated task. Cells must divide, move, and mature at specific times. Developmental genes control that process, turning on and off in a choreographed way. However, the environment influences development. A team of researchers led by Cold Spring Harbor Laboratory Associate Professor Christopher Hammell reported December 22, 2020 in the journal Current Biology how gene activity matches nutrient levels. They found a master switch developing worms use to pause growth when nutrients are scarce. When the environment improves, animals continue developing. The switch adjusts gene activity to match nutrient levels.

Roundworm embryos (purple ovals) use a master switch protein called BLMP-1 to prepare the embryo for development. BLMP-1 primes genes needed to develop into a larva and later an adult. Green dots are fluorescent tags on genes for cell growth. The larger green dots are associated with skin cells, indicating preparation for development, and the smaller dots are associated with brain cells, indicating no anticipated growth. © Natalia Stec/Hammell lab/CSHL, 2020

Caenorhabditis elegans is a tiny roundworm. In a lab, this worm develops from an embryo to a 959-cell adult in about three days. Hammell says:

“This always happens the same way. You always get 959 cells, and the patterns of those divisions that give you those cells are always done in the same manner between one animal and the next.”

The genes that direct this flexible program switch on and off in predictable patterns as an embryo morphs through several larval stages into a fully formed worm.

In the wild, developing worms can’t always depend on comfortable temperatures and plentiful food. Sometimes, development must pause until conditions improve. Hammell’s team discovered a protein called BLMP-1 that adjusts gene activity (transcription) to keep pace with development. When conditions are good, BLMP-1 levels increase and unravel stretches of DNA, so genes are more accessible. Activators then switch on the genes at the right time. “This is an anticipatory mechanism to say ‘everything’s okay, make development as robust as possible,'” Hammell explains. If conditions are not optimal, BLMP-1 levels go down, leaving genes packed tightly away, slowing or even stopping development.

The team’s experiments revealed BLMP-1 as a master regulator of thousands of genes that cycle on and off during development. Hammell says that was a surprise since his team initially set out to investigate this process in just a handful of developmental genes. BLMP-1 is unique in that it coordinates many different kinds of processes.

Hammell is not the first researcher to call attention to BLMP-1. An analogous gene is known to be overactive in some human blood cancers, where it alters the activity of a large set of genes. Hammell is hopeful that BLMP-1 in C. elegans will provide a model system to study human diseases.

Reference: http://dx.doi.org/10.1016/j.cub.2020.11.060

Provided by Cold Spring Harbor Laboratory

IMAGE RELEASE: A Blazar In the Early Universe (Astronomy)

The supersharp radio “vision” of the National Science Foundation’s Very Long Baseline Array (VLBA) has revealed previously unseen details in a jet of material ejected at three-quarters the speed of light from the core of a galaxy some 12.8 billion light-years from Earth. The galaxy, dubbed PSO J0309+27, is a blazar, with its jet pointed toward Earth, and is the brightest radio-emitting blazar yet seen at such a distance. It also is the second-brightest X-ray emitting blazar at such a distance.

The VLBA image of the blazar PSO J0309+27 is composed of data from three observations made at different radio frequencies. Red is from an observation at 1.5 GHz; green from 5 GHz; and blue from 8.4 GHz. The lower-frequency, or longer wavelength, data show the large-scale structure of the object; the intermediate- and higher-frequency data reveal increasingly smaller structures invisible to the VLBA at the lower frequency. Credit: Spingola et al.; Bill Saxton, NRAO/AUI/NSF.

In this image, the brightest radio emission comes from the galaxy’s core, at bottom right. The jet is propelled by the gravitational energy of a supermassive black hole at the core, and moves outward, toward the upper left. The jet seen here extends some 1,600 light-years, and shows structure within it.

The blazar PSO J0309+27 is in the constellation Aries. Credit: Bill Saxton, NRAO/AUI/NSF

At this distance, PSO J0309+27 is seen as it was when the universe was less than a billion years old, or just over 7 percent of its current age.

An international team of astronomers led by Cristiana Spingola of the University of Bologna in Italy, observed the galaxy in April and May of 2020. Their analysis of the object’s properties provides support for some theoretical models for why blazars are rare in the early universe. The researchers reported their results in the journal Astronomy & Astrophysics.

VLBA image of the blazar PSO J0309+27, 12.8 billion light-years from Earth. Credit: Spingola et al.; Bill Saxton, NRAO/AUI/NSF.

The National Radio Astronomy Observatory is a facility of the National Science Foundation, operated under cooperative agreement by Associated Universities, Inc.

Reference: https://www.aanda.org/articles/aa/pdf/2020/11/aa39458-20.pdf

Provided by NRAO

Controlling Cardiac Waves With Light to Better Understand Abnormally Rapid Heart Rhythms (Medicine)

Investigation of abnormally rapid heart rhythms in mice illustrates that the heart has intrinsic mechanisms that exist that lead to the self-termination of such rapid rhythms.

Over 300,000 people die each year in the U.S. due to sudden cardiac death. In many cases, sudden cardiac death is caused by abnormally rapid heart rhythms called tachycardias, which means the heart cannot pump adequate blood to the body.

In Chaos, researchers use mice to study tachycardias and find there are intrinsic mechanisms that exist in heart tissue that they hypothesize lead to the self-termination of rapid cardiac rhythm. Controllable reentry in a light-sensitive heart: (top left) Activation map during fixed delay pacing; (top right) Alternans (beat-to-beat changes) in voltage; (bottom) The same plot over a longer period shows self-terminating bursts. © Gil Bub

In Chaos, by AIP Publishing, researchers use mice to study tachycardias and find there are intrinsic mechanisms that exist in heart tissue that they hypothesize lead to the self-termination of rapid cardiac rhythm.

“A tachycardia is a heartbeat continuously activating the heart, like a toy train endlessly going around a circular track,” said co-author Leon Glass.

The researchers modeled tachycardias in a mouse heart by detecting the wave in one part of the heart and stimulating another part at a fixed time later. They discovered that small changes in the delay lead to either endless circulation or self-termination of the cardiac waves.

During the circulation of the wave and before the termination, there was often an alternation of wave characteristics, such as one cycle proceeding faster and the next being slower. The researchers used optogenetics, a set of tools that allows them to stimulate and control cardiac waves with light, rather than by standard methods of electrical stimulation.

Alternating dynamics, called alternans, in the heart have been associated in the past with initiation of tachycardias. Consequently, efforts have been made to eliminate or reduce alternans.

“Paradoxically, we find that alternans can also facilitate self-termination of tachycardia and might be beneficial,” said co-author Gil Bub.

The optical, real-time feedback control system can be used for a wide variety of innovative experiments beyond this specific research.

“We could extend the work to study control of other geometries of abnormal cardiac wave propagation such as spiral waves. It can also be applied to the nervous system where there are abnormal bursting rhythms such as epilepsy,” said co-author Leonardo Sacconi.

The team plans to build on this research in several ways, including carrying out similar experiments in cardiac cell culture and investigating how drugs impact the stability of tachycardias, characterizing the molecular and ionic mechanisms facilitating self-termination of the tachycardia, and modifying the magnitude of the alternans to analyze its role in the self-termination of tachycardia.

The article, “Universal mechanisms for self-termination of rapid cardiac rhythm,” is authored by Leon Glass, Valentina Biasci, Leonardo Sacconi, Eric N. Cytrynbaum, Daniël A. Pijnappels, Tim De Coster, Alvin Shrier, and Gil Bub. The article will appear in Chaos on Dec. 22, 2020 (DOI: 10.1063/5.0033813). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0033813.

Provided by American Institute of Physics

Study Finds Cancer Survivors Run Greater Risk of Developing, Dying from Second Cancers (Medicine)

A new American Cancer Society study finds that adult-onset cancer survivors run a greater risk of developing and dying from subsequent primary cancers (SPCs) than the general population. Cancers associated with smoking or obesity comprised a majority of SPC incidence and mortality among all survivors. The study appears in JAMA.

“These findings highlight the importance of ongoing surveillance and efforts to prevent new cancers among survivors,” said lead author, Hyuna Sung, PhD. “The number of cancer survivors who develop new cancers is projected to increase, but, until now, comprehensive data on the risk of SPCs among survivors of adult-onset cancers has been limited.”

For the study, investigators analyzed data on nearly 1.54 million cancer survivors from 1992 to 2017 from 12 Surveillance, Epidemiology, and End Results registries in the United States. The survivors analyzed were between the ages of 20 to 84 (mean age, 60.4 years), 48.8% women, and 81.5% white.

The findings suggest that among the 1,537,101 survivors, 156,442 were diagnosed with an SPC and 88,818 died of an SPC. Results found that male survivors had an 11% higher risk of developing SPCs and a 45% higher risk of dying from SPCs compared with the risk in the general population. Female survivors had a 10% higher risk of developing SPCs and a 33% higher risk of dying from SPCs.

The investigators found men who survived laryngeal cancer and Hodgkin lymphoma ran the greatest risk of developing an SPC, while men who survived gallbladder cancer ran the greatest risk of dying from an SPC. Among women, survivors of laryngeal and esophageal cancers ran the greatest risk of developing an SPC, and laryngeal cancer survivors also ran the greatest risk of SPC mortality.

Substantial variation existed in the associations of specific types of first cancers with specific types of SPC risk. However, study authors note the prevalence of smoking- and obesity-related cancers in SPC incidence and mortality. Results show the risks of smoking-related SPCs were commonly elevated among survivors of smoking-related first cancers. Among survivors of all cancers, four common smoking-related SPCs including lung, urinary bladder, oral cavity/pharynx, and esophagus, accounted for 26% to 45% of the total SPC incidence and mortality. Furthermore, lung cancer alone comprised 31% to 33% of the total mortality from SPCs. Similarly, survivors of many obesity-related cancers had an elevated risk of developing obesity-related SPCs. Among survivors of all cancers, four common obesity-related cancers colorectum, pancreas, corpus uteri, and liver, comprised 22% to 26% of total SPC mortality.

“These findings reinforce the importance of coordinated efforts by primary care clinicians to mitigate the risks of SPCs through survivorship care, with greater focus on lifestyle factors, including smoking cessation, weight management, physical activity, and healthy eating, as receipt of counseling or treatment (tobacco only) to aid in the adoption of healthy habits,” said Ahmedin Jemal, PhD, senior author of the paper.

Reference: Sung H, Hyun N, Leach CR, Yabroff R, Jemal A. Association of First Primary Cancer With Risk of Subsequent Primary Cancer Among Survivors of Adult-Onset Cancers in the United States; JAMA, 2020; doi:10.1001/jama.2020.23130. https://jamanetwork.com/journals/jama/fullarticle/2774406?guestAccessKey=00eb17bf-1fc5-4d61-acf0-b99afc8c50d5&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=122220

Provided by American Cancer Society

How a Large Protein Complex Assembles in a Cell (Biology)

A team of ETH re­search­ers led by Karsten Weis has de­veloped a method that al­lows them to study the as­sembly pro­cess for large pro­tein com­plexes in de­tail for the first time. As their case study, the bio­lo­gists chose one of the largest cel­lu­lar com­plexes: the nuc­lear pore com­plex in yeast cells.

The nuc­lear pore com­plexes (or­ange struc­tures), some of which are in the pro­cess of as­sembly, are among the largest pro­tein com­plexes in a cell. (Visu­al­isa­tion: Olga V Posukh, In­sti­tute of Mo­lecu­lar and Cel­lu­lar Bio­logy, Nov­os­ibirsk)

Cells produce a great number of different protein complexes, each of which is made up of many individual proteins. These protein complexes, like ribosomes for example, are what regulate almost all of a cell’s life-sustaining biological functions.

Biologists have succeeded in determining the structure of many of these complexes, but there is less research so far on how the individual proteins assemble and then change over time. Conventional approaches have thus far proved insufficient for studying the exact course that these reactions in cells take, especially where large complexes are concerned.

A group of ETH researchers led by Karsten Weis and research associate Evgeny Onischenko at ETH Zurich’s Institute of Biochemistry are now presenting a new approach. Their method makes it possible to track the dynamics of protein complex assemblies, even for very large ones, with high temporal resolution. The study has just been published in the journal Cell.

Inspired by metabolic analysis

The ETH researchers call their new approach KARMA, which stands for kinetic analysis of incorporation rates in macromolecular assemblies and is based on methods for investigating metabolic processes. Scientists researching metabolism have long used radioactive carbon in their work, e.g., to label glucose molecules, which cells then take up and metabolise. The radioactive labelling enables researchers to track where and at what point in time the glucose molecules or their metabolites appear.

“This type of research inspired us to apply a similar principle in exploring the reactions that take place in the assembly of protein complexes,” Weis explains. In their approach, the ETH researchers work with labelled amino acids, the fundamental building blocks of proteins, which contain heavier carbon and nitrogen isotopes. In a culture of yeast cells, the team replaces the lightweight amino acids with their heavier counterparts. The yeast uses these heavy amino acids in protein synthesis, which shifts the molecular weight of all newly produced proteins.

A time scale for the assembly of a complex

To isolate protein complexes, the researchers remove yeast cells from the cultures at regular intervals and employ mass spectrometry to measure the tiny weight difference between molecules with heavier amino acids and those without. This indicates the age of a protein in a complex. Basically, the older the protein, the earlier it was incorporated into the complex. Based on these age differences, the researchers apply kinetic state models to ultimately reconstruct the precise assembly sequence of a given protein complex.

As a case study to validate their method, Weis and his team chose the nuclear pore complex in yeast cells. This structure has some 500 to 1,000 elements composed of about 30 different proteins each in multiple copies, thus making it one of the largest known protein complexes.

Using KARMA, the ETH biochemists were able to obtain a detailed map of which modules are integrated into the structure and when. One of their findings was a hierarchical principle: individual proteins form subunits within a very short time, which then assemble from the centre out to the periphery in a specific sequence.

Durable scaffold

“We’ve demonstrated for the first time that some proteins are used very quickly in the assembly of the pore complex, while others are incorporated only after about an hour. That’s an incredibly long time,” Weis says. A yeast cell divides every 90 minutes, which means it would take almost a whole generation to complete assembly of this vital pore complex. Precisely why the assembly of new pores takes so long in relation to the yeast reproduction cycle is not known.

The ETH researchers also show that once assembly of the pore is complete, parts of the complex are highly stable and durable – in the inner scaffold, for example, hardly any components are replaced during its lifetime. By contrast, proteins at the periphery of the nuclear pore complex are frequently replaced.

Defective nuclear pores facilitate disease

Nuclear pores are some of the most important protein complexes in cells, as they are responsible for the exchange of substances and molecules between the cell nucleus and cytoplasm. For example, they transport messenger RNA from the nucleus to the cellular machinery outside the nucleus, which needs these molecules as blueprints for new proteins.

Moreover, nuclear pores play direct and indirect roles in human disease. Accordingly, changes in the nuclear pore and its proteins can impact the development of conditions like leukaemia, diabetes or neurodegenerative diseases such as Alzheimer’s. “Generally speaking, though, the reasons why pore defects cause these disease patterns are not well understood,” Weis says, explaining that KARMA might help to gain deeper insight into such issues in the future.

Versatile platform

“Although we applied KARMA to only one protein complex in this study, we’re excited about its future applications. Our method will now enable us to decipher the sequence of a whole host of biological processes,” Weis says. Their technique can be used, for example, to study molecular events that occur during the infection cycle of viruses such as COVID-19 and potentially help to find new drug candidates that break that cycle.

The new method can also be applied to other biological molecules besides proteins, such as RNA or lipids.

Reference: Onischenko E, Noor E, Fischer JS, Gillet L, Wojtynek M, Vallotton P, Weis K: Maturation Kinetics of a Multiprotein Complex Revealed by Metabolic Labeling, Cell, Available online 16 December 2020. DOI: 10.1016/j.cell.2020.11.001

Provided by ETH Zurich