Nav: Home

Scientists reveal how cell corrects errors made in gene transcription

May 03, 2016

RNA polymerase II (Pol II), a key enzyme in our gene expression, is responsible for transcribing DNA into messenger RNA. Errors in transcription can cause deleterious effect upon repeated translation of erroneous mRNA into protein. Transcription infidelity may result in aging and human diseases such as cancer. During transcription, Pol II can detect the mis-incorporated RNA and backtrack to correct errors to ensure that each messenger RNA created will match with template DNA. However, it remains largely a mystery how Pol II controls the fidelity of gene transcription.

Scientists from the Hong Kong University of Science and Technology (HKUST) elucidated the dynamics of backtracking at atomistic level by building a kinetic model (Markov State Model) based on extensive molecular dynamics simulations. They discovered that Pol II backtracking occurs in a stepwise mode, where first the RNA moves away from the active site (reaching a "frayed" state) before the enzyme can reach the backtracked state. They also found that the rate-limiting step of the process is the transition from the frayed state to the final backtracked.

Their findings were published in Nature Communications on April 19, 2016 (DOI: 10.1038/ncomms11244).

"We found that a critical amino acid (Rpb1 Threonine 831) serves as the sensing probe to detect the weak interaction between the mis-incorporated RNA and the template DNA. The bending motion of bridge helix, the protein motif where the important Threonine locates, promotes the RNA to go to the frayed state," said Xuhui Huang, associate professor of chemistry at HKUST and leader of the research group. "We further validated the predictions from our simulations by site-directed mutagenesis experiments and transcript cleavage assays in collaboration with Prof. Dong Wang's group from UCSD."

"This work requires large-scale high-performance computing resources: the ~50 microseconds of simulations contains 25 billion MD steps, which were computed on 10,000 CPU cores for 4 weeks on the Shaheen Supercomputer at KAUST (Ranked #7 worldwide in July 2015) in collaboration with Prof. Xin Gao's group. Moreover, the Markov State Model enables us to identify intermediate conformational states and kinetics of backtracking from this massive MD simulation dataset. " said Huang.

"Our results will provide insight into the fundamental mechanisms of transcription, and open up perspectives for understanding human diseases and aging problems related to transcription infidelity," said Huang. "We could also go beyond the one-nucleotide backtracking event and study the backtracking mechanisms for two or even more RNA 3?-end nucleotides, which may give insight into the molecular mechanisms of the transcriptional pausing and arrest. It would also be important to investigate the backtracking mechanisms for different mutagenic DNA lesions, such as 8-oxoG and O6-methyguanine (O6-mdG) etc., and how some of these lesions can escape Pol II proofreading."

Hong Kong University of Science and Technology

Related Aging Articles:

Researchers discover new cause of cell aging
New research from the USC Viterbi School of Engineering could be key to our understanding of how the aging process works.
Deep Aging Clocks: The emergence of AI-based biomarkers of aging and longevity
The advent of deep biomarkers of aging, longevity and mortality presents a range of non-obvious applications.
Intelligence can link to health and aging
For over 100 years, scientists have sought to understand what links a person's general intelligence, health and aging.
Putting the brakes on aging
Salk Institute researchers have developed a new gene therapy to help decelerate the aging process.
New insights into the aging brain
A group of scientists at the Gladstone Institutes investigated why the choroid plexus contains so much more klotho than other brain regions.
More Aging News and Aging Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...