̽��ֱ�� of Cambridge - Shankar Balasubramanian

10 Cambridge spinouts changing the story of cancer

skbf2 — Thu, 17 Oct 2024 12:57:43 +0000

10 Cambridge spinouts on putting their research into practice to improve outcomes for cancer patients - and why Cambridge is a great place to do this.

DNA sequencing method lifts ‘veil’ from genome black box

cr696 — Mon, 23 Jan 2023 16:00:00 +0000

In a paper published in the journal Nature Biotechnology, ̽��ֱ�� of Cambridge researchers have outlined a new DNA sequencing method that can detect where and how small molecule drugs interact with the targeted genome.

“Understanding how drugs work in the body is essential to creating better, more effective therapies,” said co-first author Dr Zutao Yu from the Yusuf Hamied Department of Chemistry. “But when a therapeutic drug enters a cancer cell with a genome that has three billion bases, it’s like entering a black box.”

̽��ֱ��powerful method, called Chem-map, lifts the veil of this genomic black box by enabling researchers to detect where small molecule drugs interact with their targets on the DNA genome.

Each year, millions of cancer patients receive treatment with genome-targeting drugs, such as doxorubicin. But despite decades of clinical use and research, the molecular mode of action with the genome is still not well-understood.

“Lots of life-saving drugs directly interact with DNA to treat diseases such as cancer,” said co-first author Dr Jochen Spiegel. “Our new method can precisely map where drugs bind to the genome, which will help us to develop better drugs in the future.”

Chem-map allows researchers to conduct in situ mapping of small molecule-genome interactions with unprecedented precision, by using a strategy called small-molecule-directed transposase Tn5 tagmentation. This detects the binding site in the genome where a small molecule binds to genomic DNA or DNA-associated proteins.

In the study, the researchers used Chem-map to determine the direct binding sites in human leukaemia cells of the widely used anticancer drug doxorubicin. ̽��ֱ��technique also showed how the combined therapy of using doxorubicin on cells already exposed to the histone deacetylase (HDAC) inhibitor tucidinostat could have a potential clinical advantage.

̽��ֱ��technique was also used to map the binding sites of certain molecules on DNA G-quadruplexes, known as G4s. G4s are four-stranded secondary structures that have been implicated in gene regulation, and could be possible targets for future anti-cancer treatments.

“I am so proud that we have been able to solve this longstanding problem – we have established a highly efficient approach which will open many paths for new research,” said Yu.

Professor Sir Shankar Balasubramanian, who led the research, said: “Chem-map is a powerful new method to detect the site in the genome where a small molecule binds to DNA or DNA-associated proteins. It provides enormous insights on how some drug therapies interact with the human genome, and makes it easier to develop more effective and safer drug therapies.”

Reference:
Zutao Yu, Jochen Spiegel et al. 'Chem-map profiles drug binding to chromatin in cells.' Nature Biotechnology (2023). DOI: 10.1038/s41587-022-01636-0

Many life-saving drugs directly interact with DNA to treat diseases such as cancer, but scientists have struggled to detect how and why they work – until now.

KTSDESIGN/SCIENCE PHOTO LIBRARY via Getty Images

Illustration of DNA molecules

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Four Cambridge researchers recognised in the 2022 Breakthrough Prizes

sc604 — Thu, 09 Sep 2021 11:59:47 +0000

Professors Shankar Balasubramanian and David Klenerman, from Cambridge’s Yusuf Hamied Department of Chemistry, have been awarded the 2022 Breakthrough Prize in Life Sciences – the world’s largest science prize – for the development of next-generation DNA sequencing. They share the award with Pascal Mayer, from the French company Alphanosos.

In addition, Professor Suchitra Sebastian, from the Cavendish Laboratory, and Professor Jack Thorne, from the Department of Pure Mathematics and Mathematical Statistics, have been recognised with the New Horizons Prize, awarded to outstanding early-career researchers.

Professor Suchitra Sebastian has been awarded the 2022 New Horizons in Physics Prize for high precision electronic and magnetic measurements that have profoundly changed our understanding of high temperature superconductors and unconventional insulators.

Professor Jack Thorne has been awarded the 2022 New Horizons in Mathematics Prize, for transformative contributions to diverse areas of algebraic number theory, and in particular for the proof, in collaboration with James Newton, of the automorphy of all symmetric powers of a holomorphic modular newform.

Professors Balasubramanian and Klenerman co-invented Solexa-Illumina Next Generation DNA Sequencing (NGS), technology that has enhanced our basic understanding of life, converting biosciences into ‘big science’ by enabling fast, accurate, low-cost and large-scale genome sequencing – the process of determining the complete DNA sequence of an organism’s make-up. They co-founded the company Solexa to make the technology available to the world.

̽��ֱ��benefits to society of rapid genome sequencing are huge. ̽��ֱ��almost immediate identification and characterisation of the virus which causes COVID-19, rapid development of vaccines, and real-time monitoring of new genetic variants would have been impossible without the technique Balasubramanian and Klenerman developed.

̽��ֱ��technology has had – and continues to have – a transformative impact in the fields of genomics, medicine and biology. One measure of the scale of change is that it has allowed a million-fold improvement in speed and cost when compared to the first sequencing of the human genome. In 2000, sequencing of one human genome took over 10 years and cost more than a billion dollars: today, the human genome can be sequenced in a single day at a cost of less than $1,000. More than a million human genomes are sequenced at scale each year, thanks to the technology co-invented by Professors Balasubramanian and Klenerman, meaning we can understand diseases much better and much more quickly. Earlier this year, they were awarded the Millennium Technology Prize. Balasubramanian is also based at the Cancer Research UK Cambridge Institute, and is a Fellow of Trinity College. Klenerman is a Fellow of Christ's College.

Professor Sebastian’s research seeks to discover exotic quantum phases of matter in complex materials. Her group’s experiments involve tuning the co-operative behaviour of electrons within these materials by subjecting them to extreme conditions including low temperature, high applied pressure, and intense magnetic field.

Under these conditions, her group can take materials that are quite close to behaving like a superconductor – perfect, lossless conductors of electricity – and ‘nudge’ them, transforming their behaviour.

“I like to call it quantum alchemy – like turning soot into gold,” Sebastian said. “You can start with a material that doesn’t even conduct electricity, squeeze it under pressure, and discover that it transforms into a superconductor. Going forward, we may also discover new quantum phases of matter that we haven’t even imagined.”

In addition to her physics research, Sebastian is also involved in theatre and the arts. She is Director of the Cavendish Arts-Science Project, which she founded in 2016. ̽��ֱ��programme has been conceived to question and explore material and immaterial universes through a dialogue between the arts and sciences.

“Being awarded the New Horizons Prize is incredibly encouraging, uplifting and joyous,” said Sebastian. “It recognises a discovery made by our team of electrons doing what they're not supposed to do. It's gone from the moment of elation and disbelief at the discovery, and then trying to follow it through, when no one else quite thinks it’s possible or that it could be happening. It’s been an incredible journey, and having it recognised in this way is incredibly rewarding.”

Professor Jack Thorne is a number theorist in the Department of Pure Mathematics and Mathematical Statistics. One of the most significant open problems in mathematics is the Riemann Hypothesis, which concerns Riemann’s zeta function. Today we know that the zeta function is intimately tied up with questions concerning the statistical distribution of prime numbers, such as how many prime numbers there are, how closely they can be found on the number line. A famous episode in the history of the Riemann Hypothesis is Freeman Dyson’s observation that the zeroes of the zeta function appear to obey statistical laws arising from the theory of random matrices, which had first been studied in theoretical physics.

In 1916, during his time in Cambridge, Ramanujan wrote down an analogue of the Riemann zeta function, inspired by his work on the number of ways of expressing a given number as a sum of squares (a problem with a rich classical history), and made some conjectures as to its properties, which have turned out to be related to many of the most exciting developments in number theory in the last century. Actually, there are a whole family of zeta functions, the properties of which control the statistics of the sums of squares problem. Thorne's work, recognised in the prize citation, essentially shows for Ramanujan’s zeta functions what Riemann proved for his zeta function in 1859.

Taking a broader view, Ramanujan’s zeta functions are now seen to fit into the framework of the Langlands Program. This is a series of conjectures, made by Langlands in the 1960’s, which have been described as a “grand unified theory of mathematics”, and which can be used to explain any number of phenomena in number theory. Another famous example is Wiles proof, in 1994, of Fermat’s Last Theorem. Nowadays the essential piece of Wiles’ work is seen as progress towards a small part of the Langlands program. Thorne's work establishes part of Langlands’ conjectures for a class of objects including Ramanujan’s Delta function.

"I am deeply honoured to be awarded the New Horizons Prize for my work in number theory," said Thorne. "Number theory is a subject with a rich history in Cambridge and I feel very fortunate to be able to make my own contribution to this tradition."

For the tenth year, the Breakthrough Prize recognises the world’s top scientists. Each prize is US $3 million and presented in the fields of Life Sciences, Fundamental Physics (one per year) and Mathematics (one per year). In addition, up to three New Horizons in Physics Prizes, up to three New Horizons in Mathematics Prizes and up to three Maryam Mirzakhani New Frontiers Prizes are given out to early-career researchers each year, each worth US $100,000. ̽��ֱ��Breakthrough Prizes were founded by Sergey Brin, Priscilla Chan and Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki.

Four ̽��ֱ�� of Cambridge researchers – Professors Shankar Balasubramanian, David Klenerman, Suchitra Sebastian and Jack Thorne – have been recognised by the Breakthrough Prize Foundation for their outstanding scientific achievements.

L-R: Millennium Technology Prize, Nick Saffell, Jack Thorne

L-R: David Klenerman, Shankar Balasubramanian, Suchitra Sebastian, Jack Thorne

Yes

Cambridge researchers awarded the Millennium Technology Prize

sc604 — Tue, 18 May 2021 14:32:48 +0000

̽��ֱ�� of Cambridge chemists Shankar Balasubramanian and David Klenerman have been jointly awarded the 2020 Millennium Technology Prize, one of the world’s most prestigious science and technology prizes, by Technology Academy Finland (TAF).

̽��ֱ��global prize, awarded at two-year intervals since 2004 to highlight the impact of science and innovation on society, is worth €1 million. Of the nine previous winners of the Millennium Technology Prize, three have subsequently gone on to win a Nobel Prize. This is the first time that the prize has been awarded to more than one recipient for the same innovation, celebrating the significance of collaboration. ̽��ֱ��announcement of the 2020 award was delayed due to the COVID-19 pandemic.

̽��ֱ��technology has had – and continues to have – a transformative impact in the fields of genomics, medicine and biology. One measure of the scale of change is that it has allowed a million-fold improvement in speed and cost when compared to the first sequencing of the human genome. In 2000, sequencing of one human genome took over 10 years and cost more than a billion dollars: today, the human genome can be sequenced in a single day at a cost of $1,000. More than a million human genomes are sequenced at scale each year, thanks to the technology co-invented by Professors Balasubramanian and Klenerman, meaning we can understand diseases much better and much more quickly.

Professor Sir Shankar Balsubramanian FRS from the Yusuf Hamied Department of Chemistry, Cancer Research UK Cambridge Institute and a Fellow of Trinity College, said: “I am absolutely delighted at being awarded the Millennium Technology Prize jointly with David Klenerman, but it’s not just for us, I’m happy on behalf of everyone who has contributed to this work.”

Professor Sir David Klenerman FMedSci FRS from the Yusuf Hamied Department of Chemistry, and a Fellow of Christ’s College, said: “It’s the first time that we’ve been internationally recognised for developing this technology. ̽��ֱ��idea came from Cambridge and was developed in Cambridge. It’s now used all over the world, so I’m delighted largely for the team of people who worked on this project and contributed to its success.”

Next-generation sequencing involves fragmenting sample DNA into many small pieces that are immobilized on the surface of a chip and locally amplified. Each fragment is then decoded on the chip, base-by-base, using fluorescently coloured nucleotides added by an enzyme. By detecting the colour-coded nucleotides incorporated at each position on the chip with a fluorescence detector – and repeating this cycle hundreds of times – it is possible to determine the DNA sequence of each fragment.

̽��ֱ��collected data is then analysed using computer software to assemble the full DNA sequence from the sequence of all these fragments. ̽��ֱ��NGS method’s ability to sequence billions of fragments in a parallel fashion makes the technique fast, accurate and cost-efficient. ̽��ֱ��invention of NGS was a revolutionary approach to the understanding of the genetic code in all living organisms.

Next-generation sequencing provides an effective way to study and identify new coronavirus strains and other pathogens. With the emergence of the COVID-19 pandemic, the technology is now being used to track and explore mutations in the coronavirus. This work has helped the creation of multiple vaccines now being administered worldwide and is critical to the creation of new vaccines against new dangerous viral strains. ̽��ֱ��results will also be used to prevent future pandemics.

̽��ֱ��technology is also allowing scientists and researchers to identify the underlying factors in individuals that contribute to their immune response to COVID-19. This information is essential to unravelling the reason behind why some people respond much worse to the virus than others.

NGS technology has revolutionised global biological and biomedical research and has enabled the development of a broad range of related technologies, applications and innovations. Due to its efficiency, NGS is widely adopted in healthcare and diagnostics, such as cancer, rare diseases, infectious medicine, and sequencing-based non-invasive prenatal testing.

It is increasingly used to define the genetic risk genes for patients with a rare disease and to define new drug targets for disease in defined patient groups. NGS has also contributed to the creation of new and powerful biological therapies like antibodies and gene therapies.

In the field of cancer, NGS is becoming the standard analytical method for defining personalised therapeutic treatment. ̽��ֱ��technology has dramatically improved our understanding of the genetic basis of many cancers and is often used both for clinical tests for early detection and diagnostics both from tumours and patients’ blood samples.

In addition to medical applications, NGS has also had a major impact on all of biology as it allows the clear identification of thousands of organisms in almost any kind of sample, which is important for agriculture, ecology and biodiversity research.

Academy Professor Päivi Törmä, Chair of the Millennium Technology Prize Selection Committee, said: “ ̽��ֱ��future potential of NGS is enormous and the exploitation of the technology is still in its infancy. ̽��ֱ��technology will be a crucial element in promoting sustainable development through personalisation of medicine, understanding and fighting killer diseases, and hence improving the quality of life. Professor Balasubramanian and Professor Klenerman are worthy winners of the prize.”

Professor Marja Makarow, Chair of Technology Academy Finland said: “Collaboration is an essential part of ensuring positive change for the future. Next Generation Sequencing is the perfect example of what can be achieved through teamwork and individuals from different scientific backgrounds coming together to solve a problem.

“ ̽��ֱ��technology pioneered by Professor Balasubramanian and Professor Klenerman has also played a key role in helping discover the coronavirus’s sequence, which in turn enabled the creation of the vaccines – itself a triumph for cross-border collaboration – and helped identify new variants of COVID-19.”

Tomorrow (19 May 2021) Professors Balasubramanian and Klenerman will deliver the Millennium Technology Prize Lecture, talking about their innovation, at 14:30 at the Millennium Innovation Forum. ̽��ֱ��lecture can be accessed here.

British duo Professor Shankar Balasubramanian and Professor David Klenerman have been awarded the Millennium Technology Prize for their development of revolutionary DNA sequencing techniques.

Journeys of Discovery: Rapid genome sequencing

Millennium Technology Prize

David Klenerman and Shankar Balasubramanian receiving the MTP prize

Yes

Journeys of discovery: rapid genome sequencing

lw355 — Tue, 18 May 2021 14:24:34 +0000

David Klenerman and Shankar Balasubramanian talk about their discovery of a revolutionary DNA sequencing technology – and the global impact that continues to surprise them.

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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̽��ֱ�� people recognised in 2017 New Year Honours list

Anonymous — Fri, 30 Dec 2016 22:30:00 +0000

Ottoline Leyser (above left) is Director of the Sainsbury Laboratory. She becomes a Dame Commander of the Order of the British Empire (DBE) for services to Plant Science, Science in Society and Equality and Diversity in Science.

Dame Ottoline’s research aims to understand how plants adjust their growth and development to suit the environmental conditions in which they are growing. In particular, she is studying how plants change the number of shoot branches they produce depending on factors such as nutrient supply and damage to the main shoot. She is particularly interested in the roles and mechanisms of action of plant hormones such as auxin. She is a Fellow of Clare College.

“This is a huge honour,” said Dame Ottoline. “It’s so uplifting that things I really care about can be celebrated in this extraordinary way. Science has such a lot to offer the world, which makes it really important that science is open to all, so that everyone can contribute to the process and benefit from the results.”

Shankar Balasubramanian (above right) is Herchel Smith Professor of Medicinal Chemistry in the Department of Chemistry the ̽��ֱ�� of Cambridge, Senior Group Leader at the Cancer Research UK Cambridge Institute and Fellow of Trinity College. He has been named a Knight Bachelor for services to science and medicine. He co-invented next generation sequencing which has provided the most transformative change in biology and medicine for several decades, and has led to the $1000 dollar human genome. He has also made important contributions to four-stranded DNA, known as G-quadruplexes, and their role in cancer.

“It is a great honour for me and a wonderful acknowledgement of the research and I have carried out in Cambridge with my co-workers and collaborators over the past two decades,” said Sir Shankar. “I was particularly pleased to see recognition of our basic science and its impact on medicine, as I am jointly appointed between the Departments of Chemistry and Medicine.”

Professor John Pyle, Head of the Department of Chemistry, is appointed CBE for services to Atmospheric Chemistry and Environmental Science. Professor Pyle’s research uses of state-of-the-art numerical models, run on supercomputers, to study the processes controlling the present state of the atmosphere and its evolution. He is a Fellow of St Catharine’s College.

"I'm delighted, of course," said Pyle. "We are the best chemistry department in the country and one of the very best in the world. It's fantastic for the department to get recognition for that work."

Professor John Spencer, Bye Fellow in Law at Murray Edwards College, Life Fellow of Selwyn College and Professor Emeritus of Law, is also appointed CBE for services to the Reform of Law Concerning Child Witnesses. His interests include criminal law, criminal evidence, comparative criminal law, and the law of tort. He has been involved in a great many of projects for law reform, including as a Consultant to the Law Commission on a project to reform the hearsay rule in 1995; as a member of a committee of experts set up by the European Commission to study fraud on the Community finances, and as a member of the Home Office group that drafted “Achieving Best Evidence in Criminal Proceedings” (1999-2001). He was also a consultant to the Auld Review of Criminal Courts in 2001.

Professor Jane Francis, Director of the British Antarctic Survey and Fellow of Darwin College, is appointed Dame Commander of the Order of St Michael and St George for services UK Polar Science and Diplomacy. She was only the fourth woman in history to receive the Polar Medal in 2002. Since being appointed Director of BAS in 2013, she has had a dual role of ensuring UK scientific polar excellence and promoting British sovereign interests in Antarctica. As the first female Director, she has embraced gender diversity and has been an inspiration and influential figure in the British scientific establishment. She is globally recognised as a leader in Polar Science and has made a significant contribution to our understanding of palaeo-climates. She has also undertaken a wide range of international roles which further promote the UK’s polar interests and sits on polar science advisory boards for other countries.

Professor Peter Weissberg, former Medical Director of the British Heart Foundation and Fellow of Wolfson College, has been awarded a CBE for services to medical research and cardiovascular health. Prior to his tenure at the BHF, Professor Weissberg established the Division of Cardiovascular Medicine at Cambridge and spent ten years as the ̽��ֱ��’s first BHF Professor of Cardiovascular Medicine.

Distinguished members of the ̽��ֱ�� of Cambridge have been named in the 2017 New Year Honours list, announced today. Professor Ottoline Leyser, Professor Shankar Balasubramanian and Professor John Pyle are among those who have been recognised for their contributions to society.

̽��ֱ��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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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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