̽��ֱ�� of Cambridge - Robert Hänsel-Hertsch

Four-stranded DNA structures found to play role in breast cancer

cjb250 — Mon, 03 Aug 2020 15:01:09 +0000

In 1953, Cambridge researchers Francis Crick and James Watson co-authored a study published in the journal Nature which showed that DNA in our cells has an intertwined, ‘double helix’ structure. Sixty years later, a team led by Professor Sir Shankar Balasubramanian and Professor Steve Jackson, also at Cambridge, found that an unusual four-stranded configuration of DNA can occur across the human genome in living cells.

These structures form in regions of DNA that are rich in one of its building blocks, guanine (G), when a single strand of the double-stranded DNA loops out and doubles back on itself, forming a four-stranded ‘handle’ in the genome. As a result, these structures are called G-quadruplexes.

Professor Balasubramanian and colleagues have previously developed sequencing technologies and approaches capable of detecting G-quadruplexes in DNA and in chromatin (a substance comprised of DNA and proteins). They have previously shown that G-quadruplexes play a role in transcription, a key step in reading the genetic code and creating proteins from DNA. Crucially, their work also showed that G-quadruplexes are more likely to occur in genes of cells that are rapidly dividing, such as cancer cells.

Now, for the first time, the team has discovered where G-quadruplexes form in preserved tumour tissue/biopsies of breast cancer. Details of their study are published today in the journal Nature Genetics.

̽��ֱ��Cambridge team led by Professor Balasubramanian and Professor Caldas used their quantitative sequencing technology to study G-quadruplex DNA structures in 22 model tumours. These models had been generated by taking biopsies from patients at Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospital NHS Foundation Trust, then transplanting and growing the tumours in mice.

During the process of DNA replication and cell division that occurs in cancer, large regions of the genome can be erroneously duplicated several times leading to so-called copy number aberrations (CNAs). ̽��ֱ��researchers found that G-quadruplexes are prevalent within these CNAs, particularly within genes and genetic regions that play an active role in transcription and hence in driving the tumour’s growth.

Professor Balasubramanian said: “We’re all familiar with the idea of DNA’s two-stranded, double helix structure, but over the past decade it’s become increasingly clear that DNA can also exist in four-stranded structures and that these play an important role in human biology. They are found in particularly high levels in cells that are rapidly dividing, such as cancer cells. This study is the first time that we’ve found them in breast cancer cells.”

“ ̽��ֱ��abundance and location of G-quadruplexes in these biopsies gives us a clue to their importance in cancer biology and to the heterogeneity of these breast cancers,” added Dr Robert Hänsel-Hertsch who is now at the Center for Molecular Medicine Cologne, ̽��ֱ�� of Cologne, and is first author on the publication.

“Importantly, it highlights another potential weak spot that we might use against the breast tumour to develop better treatments for our patients.”

There are thought to be at least 11 subtypes of breast cancer, and the team found that each has a different pattern – or ‘landscape’ – of G-quadruplexes that is unique to the transcriptional programmes driving that particular subtype.

Professor Carlos Caldas from the Cancer Research UK Cambridge Institute, said: “While we often think of breast cancer as one disease, there are actually at least 11 known subtypes, each of which may respond in different ways to different drugs.

“Identifying a tumour’s particular pattern of G-quadruplexes could help us pinpoint a woman’s breast cancer subtype, enabling us to offer her a more personalised, targeted treatment.”

By targeting the G-quadruplexes with synthetic molecules, it may be possible to prevent cells from replicating their DNA and so block cell division, halting the runaway cell proliferation at the root of cancer. ̽��ֱ��team identified two such molecules – one known as pyridostatin and a second compound, CX-5461, which has previously been tested in a phase I trial against BRCA2-deficient breast cancer.

̽��ֱ��research was funded by Cancer Research UK.

Reference
Hänsel-Hertsch, R et al. Landscape of G-quadruplex DNA structural regions in breast cancer. Nat Gen; 3 Aug 2020; DOI: 10.1038/s41588-020-0672-8

Four-stranded DNA structures – known as G-quadruplexes – have been shown to play a role in certain types of breast cancer for the first time, providing a potential new target for personalised medicine, say scientists at the ̽��ֱ�� of Cambridge.

We’re all familiar with the idea of DNA’s two-stranded, double helix structure, but over the past decade it’s become increasingly clear that DNA can also exist in four-stranded structures and that these play an important role in human biology

Shankar Balasubramanian

Thomas Splettstoesser

Crystal structure of parallel quadruplexes from human telomeric DNA. ̽��ֱ��DNA strand (blue) circles the bases that stack together in the center around three co-ordinated metal ions (green)

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Quadruple helix form of DNA may aid in the development of targeted cancer therapies

sc604 — Mon, 12 Sep 2016 15:00:01 +0000

Scientists have identified where a four-stranded version of DNA exists within the genome of human cells, and suggest that it may hold a key to developing new, targeted therapies for cancer.

In work funded by Cancer Research UK and EMBO, the researchers, from the ̽��ֱ�� of Cambridge, found that these quadruple helix structures occur in the regions of DNA that control genes, particularly cancer genes, suggesting that they may play a role in switching genes on or off. ̽��ֱ��results, reported in the journal Nature Genetics, could also have implications for cancer diagnostics and the development of new targeted treatments.

Most of us are familiar with the double helix structure of DNA, but there is also a version of the molecule which has a quadruple helix structure. These structures are often referred to as G-quadruplexes, as they form in the regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’. These structures were first found to exist in human cells by the same team behind the current research, but at the time it was not exactly clear where these structures were found in the genome, and what their role was, although it was suspected that they had a link with certain cancer genes.

“There have been a number of different connections made between these structures and cancer, but these have been largely hypothetical,” said Professor Shankar Balasubramanian, from Cambridge’s Department of Chemistry and Cancer Research UK Cambridge Institute, and the paper’s senior author. “But what we’ve found is that even in non-cancer cells, these structures seem to come and go in a way that’s linked to genes being switched on or off.”

Starting with a pre-cancerous human cell line, the researchers used small molecules to change the state of the cells in order to observe where the G-quadruplexes might appear. They detected approximately 10,000 G-quadruplexes, primarily in regions of DNA associated with switching genes on or off, and particularly in genes associated with cancer.

“What we observed is that the presence of G-quadruplexes goes hand in hand with the output of the associated gene,” said Balasubramanian. This suggests that G-quadruplexes may play a similar role to epigenetic marks: small chemical modifications which affect how the DNA sequence is interpreted and control how certain genes are switched on or off.

̽��ֱ��results also suggest that G-quadruplexes hold potential as a molecular target for early cancer diagnosis and treatment, in particular for so-called small molecule treatments which target cancer cells, instead of traditional treatments which hit all cells.

“We’ve been looking for an explanation for why it is that certain cancer cells are more sensitive to small molecules that target G-quadruplexes than non-cancer cells,” said Balasubramanian. “One simple reason could be that there are more of these G-quadruplex structures in pre-cancerous or cancer cells, so there are more targets for small molecules, and so the cancer cells tend to be more sensitive to this sort of intervention than non-cancer cells.

“It all points in a certain direction, and suggests that there’s a rationale for the selective targeting of cancer cells.”

“We found that G-quadruplexes appear in regions of the genome where proteins such as transcription factors control cell fate and function,” said Dr Robert Hänsel-Hertsch, the paper’s lead author. “ ̽��ֱ��finding that these structures may help regulate the way that information is encoded and decoded in the genome will change the way we think this process works.”

Dr Emma Smith, Cancer Research UK’s science information manager, said: “Figuring out the fundamental processes that cancer cells use to switch genes on and off could help scientists develop new treatments that work against many types of the disease. And exploiting weaknesses in cancer cells could mean this approach would cause less damage to healthy cells, reducing potential side effects. It’s still early days, but promising leads like this are where the treatments of the future will come from.”

Reference:
Robert Hänsel-Hertsch et. al. ‘G-quadruplex structures mark human regulatory chromatin.’ Nature Genetics (2016). DOI: 10.1038/ng.3662

Researchers have identified the role that a four-stranded version of DNA may play in the role of cancer progression, and suggest that it may be used to develop new targeted cancer therapies.

It all points in a certain direction, and suggests that there’s a rationale for the selective targeting of cancer cells.

Shankar Balasubramanian

Thomas Splettstoesser

Crystal structure of parallel quadruplexes from human telomeric DNA.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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