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Scientists at UMass Chan Medical School have explained how proteins that regulate gene function called transcription factors (TF) can increase genetic mutations by competing with DNA repair operations during genome replication. Published in Cell, these findings show that this natural rivalry between TFs and DNA repair can explain, in part, why TF binding sites show an increased mutation rate compared to the rest of the genome, especially in cancer cells. 

Mutation rates vary greatly across the human genome, with some areas being far more prone to errors. Studies have shown that mutations at regulatory sites bound by TFs happen at a higher rate compared to the rest of the genome, but the reasons for this are not well understood.  

“Cancer cells accumulate a lot of mutations. Some are more important than others,” said Raluca Gordan, PhD, professor of genomics & computational biology. “Our results show that many mutations prevalent in TF binding sites are less likely to be selected for cancer cell survival, and instead are the result of a natural competition between TFs and DNA repair, which means that such mutations should not be prioritized for screening and in-depth studies by scientists.” 

The DNA mismatch repair mechanism is a crucial component in maintaining genetic fidelity from a parent cell to a daughter cell. Mismatch repair (MMR) proteins, like MutSα, scan the DNA of a daughter cell as it is being copied—a process called DNA replication—before cell division starts to ensure that it matches the parent cell. If the MMR protein finds a mistake, it signals the cell to cut out the DNA region containing the incorrect nucleotide and replace it with a correct sequence. This helps maintain genetic stability from one cell generation to the next. 

Studying single nucleotide errors, however, is challenging for scientists. These errors are very rare, occurring at most once in every 1 million cell divisions.  

“You can’t do a study based on one cell,” said Wei Zhu, PhD, a former student in Dr. Gordan’s lab at Duke University and now a postdoctoral fellow at Harvard Medical School. “You’d have to sequence millions and millions and millions of cells to assemble enough mutations to study this phenomenon.”

Additionally, modern genome sequencing technologies aren’t accurate enough for this kind of work. Even the best technologies have an error rate in the thousands, which is far higher than the 1 in a 1 million rate of replication errors Gordan and colleagues were hoping to study. For small genomic areas, such as TF sites that span only 10 to 20 base pairs, quantifying mutations that result from replication errors is practically impossible with current sequencing technologies.  

To overcome these challenges, Gordan and colleagues developed a mutagenic system using yeast genetics. This system allowed scientists to easily isolate and select cells for very specific mutations—down to the nucleotide—in TF binding sites. This technique allowed them to produce the quantity of nucleotide-specific mutated cells for testing.  

They then tested these mutations to determine how well the TF protein, versus the MMR protein MutSα, bound to the DNA mismatch errors that gave rise to the mutations. What they found was that these mismatches were preferentially bound by the TF instead of MutSα. As a result, these mismatch replication errors were less likely to be recognized and fixed by MutSα and were instead being passed down to daughter cells. In following cell generations, these unrepaired mismatches then show up as mutations.  

“From an evolutionary perspective it is easier for a cell to evolve a TF binding site than a gene,” said Dr. Zhu. “For this reason, you can understand how the TF-MMR competition that we discovered can, over time, lead to beneficial mutations that are selected and maintained by the organism. In cancer cells, however, this natural TF-MMR competition process can be problematic for two reasons. First, having more mutations in TF binding sites gives the cancer cells more mutations to select from for increased survival. Second, even when the mutations resulting from TF-MMR competition aren’t doing anything and are just along for the ride, they can obscure cancer-promoting mutations that now become harder to detect.” 

Gordan and colleagues plan to model the formation of mutations in cancer cells to identify specific mutations that are more common in cancer but cannot be explained by this newly discovered TF-MM competition mechanism.

New analyses of the samples taken from asteroid Bennu by NASA’s OSIRIS-REx have revealed new insights into its origin – and The University of Manchester’s scientists have played a key role.

A series of three new papers published this week in Nature Astronomy and Nature Geoscience, reveal that Bennu is a mix of dust formed in our solar system, organic matter from interstellar space and stardust that predates the solar system itself. The asteroid is thought to have formed from fragments of a larger parent asteroid destroyed by a collision in the asteroid belt between the orbits of Mars and Jupiter.

In the first paper, co-led by researchers at the University of Arizona and NASA’s Johnson Space Center, published in the journal Nature Astronomy, Manchester researchers studied the gases trapped inside Bennu’s samples – in particular xenon, which is a very rare gas. Their measurements showed that Bennu’s gases resembled those found in some of the most primitive meteorites found on earth and materials returned from asteroid Ryugu by Japan’s Hayabusa2 mission.

When combined with other elemental and isotopic analyses, the results suggest that Bennu’s parent body contained material from a range of origins, close to the Sun, far from the Sun, and even some grains from beyond our solar system.

The findings also show that while much of the materials in the parent asteroid had been affected by water and heat, some of the material had escaped various chemical processes and retained its original chemical signatures. Some even survived the extremely energetic collision that broke it apart and formed Bennu.

The studies also show that while some of Bennu’s original material survived unchanged, similarly, much of it was transformed by reactions with water. Minerals in its parent asteroid likely formed, dissolved, and re-formed over time, with up to 80% of Bennu’s material now made up of water-bearing minerals.

These findings were reported in a second paper the paper published in Nature Geoscience co-led by the University of Arizona and the Smithsonian’s National Museum of Natural History, and included contributions from Professor Rhian Jones at The University of Manchester.

In the third paper, co-led by Lindsay Keller at NASA’s Johnson Space Center and Michelle Thompson of Purdue University, also published in Nature Geoscience, researchers found microscopic craters and tiny splashes of once-molten rock – known as impact melts – on the sample surfaces – signs that the asteroid was bombarded by micrometeorites. These impacts, together with the effects of solar wind, are known as space weathering and occurred because Bennu has no atmosphere to protect it.

Lindsay Keller at NASA’s Johnson Space Center, said: “The surface weathering at Bennu is happening a lot faster than conventional wisdom would have it, and the impact melt mechanism appears to dominate, contrary to what we originally thought.

“Space weathering is an important process that affects all asteroids, and with returned samples, we can tease out the properties controlling it and use that data and extrapolate it to explain the surface and evolution of asteroid bodies that we haven’t visited.”

As leftovers from the formation of planets 4.5 billion years ago, asteroids like Bennu provide a valuable record of solar system history. Unlike meteorites that fall to Earth, which often burn up or are altered in the atmosphere, Bennu’s pristine samples give scientists a rare opportunity to study untouched material.

The project brings together researchers from NASA, universities and research centres around the world – including the UK, the United States, Japan and Canada – to study Bennu’s samples and unlock new insights into the origins of the solar system.