Protein complex clears potential traffic jams in RNA production, finds research

Agencies
April 6, 2019

April 6: A new research has found that a protein complex plays a key role in clearing potential traffic jams in the production of RNA.

The research was published in the journal Genes & Development.

"The 'Ccr4-Not' complex is involved in nearly every step of this process from start to finish. Our new research shows that this complex has an additional function that helps maintain normal cellular function when something goes wrong during transcription," said Joseph C. Reese, a researcher.

During the transcription of RNA from DNA, RNAPII, itself a large complex made up of multiple protein subunits, travels along the strand of DNA reading the ATCG sequence and producing a complementary strand of RNA.

If the RNAPII encounters DNA damage, which can be caused by UV radiation and other sources, it can become stuck and prevent trailing polymerases from completing transcription of the gene, similar to how a stalled car prevents traffic behind it from flowing.

If this jam cannot be cleared, multiple RNAPIIs transcribing the same gene can start to pile up in a sort of traffic jam preventing the DNA from being repaired and hampering cell function.

"Defects in this pathway have been associated with a number of diseases and human syndromes, such as Cockayne syndrome- a neurodegenerative disorder that results in growth failure, neurological developmental defects, and sensitivity to UV light," Reese added.

RNA polymerase II (RNAPII), the enzyme that produces RNA from a DNA template, can become stuck due to damage to the DNA template, and these jams must be cleared to restore gene expression and normal cell function.

New research shows that the master regulatory complex, 'Ccr4-Not' performs this task, associating with RNAPII during the transcription of RNA from DNA and marking RNAPII for degradation when it becomes stuck, allowing the DNA to be repaired and normal cell function to resume.

"Normal cellular functions rely on what is sometimes called the 'central dogma of biology,'" said Reese.

The researchers used genetic methods and reconstitution biochemistry- a method whereby purified components of a cellular process can be added- taken away, and mixed in a precisely controlled manner to identify exactly how they function to show that 'Ccr4-Not' recruits factors that mark RNAPII with a small signalling molecule called ubiquitin.Attachment of ubiquitin to RNAPII triggers other cellular components to degrade the enzyme, clearing the jam.

"Mutating members of the 'Ccr4-Not' complex makes cells more sensitive to agents that damage the genome, but because 'Ccr4-Not' is involved in so many aspects of gene regulation it wasn't clear until now what its precise role was," said Reese.

"The fact that 'Ccr4-Not' recruited the destruction machinery to RNAPII was a surprising result, and suggests it acts as a tow truck to remove traffic jams throughout the genome," he added.

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Agencies
June 22,2020

A team of scientists has produced first open source all-atom models of full-length COVID-19 Spike protein that facilitates viral entry into host cells – a discovery that can facilitate a faster vaccine and antiviral drug development.

The group from Seoul National University in South Korea, University of Cambridge in the UK and Lehigh University in the US produced the first open-source all-atom models of a full-length S protein.

The researchers say this is of particular importance because the S protein plays a central role in viral entry into cells, making it a main target for vaccine and antiviral drug development.

"Our models are the first full-length SARS-CoV-2 spike (S) protein models that are available to other scientists," said Wonpil Im, a professor in Lehigh University.

"Our team spent days and nights to build these models very carefully from the known cryo-EM structure portions. Modeling was very challenging because there were many regions where simple modeling failed to provide high-quality models," he wrote in a paper published in The Journal of Physical Chemistry B.

Scientists can use the models to conduct innovative and novel simulation research for the prevention and treatment of Covid-19.

Though the coronavirus uses many different proteins to replicate and invade cells, the Spike protein is the major surface protein that it uses to bind to a receptor.

The total number of global COVID-19 cases was nearing 9 million, while the deaths have increased to over 467,000, according to the Johns Hopkins University.

With 2,279,306 cases and 119,967 deaths, the US continues with the world's highest number of COVID-19 infections and fatalities, according to the CSSE.

Brazil comes in the second place with 1,083,341 infections and 50,591 deaths.

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Agencies
June 11,2020

The World Health Organisation (WHO) Director-General Tedros Adhanom Ghebreyesus said that more research needs to be done to better understand the extent to which COVID-19 is being spread by people who don't show symptoms.

"Since early February, we have said that asymptomatic people can transmit COVID-19, but that we need more research to establish the extent of asymptomatic transmission," the WHO chief said at a virtual press conference from Geneva on Wednesday, Xinhua news agency reported.

"That research is ongoing, and we're seeing more and more research being done," he added.

Saying that the world has been achieving a lot in knowing the new virus, the WHO chief told reporters that "there's still a lot we don't

"WHO's advice will continue to evolve as new information becomes available," he said.

Tedros stressed that the most critical way to stop transmission is to find, isolate and test people with symptoms, and trace and quarantine their contacts.

"Many countries have succeeded in suppressing transmission and controlling the virus doing exactly this," Tedros said.

Meanwhile, Michael Ryan, executive director of WHO Health Emergencies Program, said Wednesday that the COVID-19 pandemic is still evolving.

"If we look at the numbers... this pandemic is still evolving. It is growing in many parts of the world," he said. "We have deep concerns that health systems of some countries are struggling, under a huge strain and require our support, our help and our solidarity."

He said "each and every country has a different combination of risks and opportunities, and it's really down to national authorities to carefully consider where they are in the pandemic."

In Europe, the risk issue now are about travels and the opening of the schools, around risk management, mass gathering, surveillance and contact tracing, said the WHO official.

In Southeast Asian countries, where to a great extent transmissions have been under control, governments are more concerned about the re-emergence of clusters, while in South America, the issue of PPE for health workers has not gone away, said Ryan.

As regards Africa, Ryan said the death rates have been very low in the past week, but the health system can be overwhelmed, as it would have to cope with other diseases such as malaria.

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Agencies
June 19,2020

While coughing, fever and difficulty in breathing are common symptoms of COVID-19, a new case study has found that pink eye is also a reason to be tested for the disease.

The study, published in the Canadian Journal of Ophthalmology, determined that conjunctivitis and keratoconjunctivitis can also be primary symptoms of COVID-19.

The researchers noted that in March, a 29-year-old woman arrived at the Royal Alexandra Hospital's Eye Institute of Alberta with a severe case of conjunctivitis and minimal respiratory symptoms.

After the patient had undergone several days of treatment with little improvement -- and after it had been determined that the woman had recently returned home from Asia -- a resident ordered a COVID-19 test.

The test came back positive, according to the researchers.

"What is interesting in this case, and perhaps very different to how it had been recognised at that specific time, was that the main presentation of the illness was not a respiratory symptom. It was the eye," said Carlos Solarte, an assistant professor at the University of Alberta in Canada.

"There was no fever and no cough, so we weren't led to suspect COVID-19 at the beginning. We didn't know it could present primarily with the eye and not with the lungs," Solarte said.

Academic studies at the outset of the pandemic identified conjunctivitis as a secondary symptoms in about 10 to 15 per cent of COVID-19 cases, he said.

Since then, scientists have gained greater knowledge of how the virus can transmit through and affect the body's mucous membrane system, of which the conjunctiva -- the clear, thin membrane that covers the front surface of the eye -- is an extension.

While the finding provides important new health information for the public, it also makes eye exams more complicated for ophthalmologists and staff, the researchers noted.

"The patient in this case eventually recovered well without any issues. But several of the residents and staff who were in close contact with the patient had to be under quarantine," said Solarte.

"Fortunately, none who were involved in her care also tested positive," he said.

Patients coming into an eye clinic with conjunctivitis and keratoconjunctivitis are now treated as potential cases of COVID-19 and extra precautions are taken by staff, according to the researchers.

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