2024/12/01 by Ashok R. Venkitaraman · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Cell death mechanisms and regulation #DNA Repair Mechanisms #PARP inhibition in cancer therapy
paper · pdf · doi:10.1242/dmm.052164
openalex publication_date 2024/12/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
Ashok VenkitaramanAshok Venkitaraman has made seminal discoveries elucidating the tumour suppressive mechanisms that maintain genome integrity through his pivotal studies on the breast cancer gene BRCA2, thereby illuminating the role of a class of genes often inactivated in human cancers. Ashok initially studied medicine at the Christian Medical College, Vellore, India. He then moved into fundamental research by completing a PhD at University College London in Marc Feldman's laboratory. Ashok was first a group leader at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) in Cambridge from 1991 to 1998. In 1998, he was elected as the first holder of the Ursula Zoellner Professorship at the University of Cambridge, and was later the Director of the MRC Cancer Unit and Joint Director of the Hutchison/MRC Research Centre from 2006 to 2019. In 2020, Ashok moved his laboratory to Singapore, where he is Director of the Cancer Science Institute of Singapore and Distinguished Professor of Medicine at the Yong Loo Lin School of Medicine, National University of Singapore. He is also Research Director in the Institute of Molecular and Cell Biology at the Agency for Science, Technology and Research (A*STAR). Owing to his prominent research achievements, Ashok has been elected a Fellow of the Academy of Medical Sciences and a Member of the European Molecular Biology Organization (EMBO). In 2017, he was awarded the Basser Global Prize for his groundbreaking research uncovering how BRCA2 suppresses cancer by protecting genome integrity. Ashok's work-advancing drug discovery has led to several spin-out companies, including PhoreMost and Sentinel Oncology. Here, we discuss his outstanding research journey, how this is translating to tangible clinical outcomes and how these outcomes can be shared globally. What made you decide to move into fundamental and translational research after studying medicine?I trained in a small medical school, in a small town in the south of India. Unusually – because the Christian Medical College ran an innovative training programme for its students that took us out into the local villages – this experience exposed me to what it's like to practice medicine in rural India. For me, that was a revelation. It led to the realisation that, in the face of such extreme need, often driven by socioeconomic circumstances, I could do little as a medical practitioner. Not surprisingly, I turned towards research, with the ambition that my work could impact more people than I would have ever been able to help as a clinician.Anything I've achieved in my career was founded on the generosity and mentorship of many individuals. In India, when I was training at medical school, research was not part of the curriculum. At that time, Jacob John was the Professor of Virology at the Christian Medical College Hospital in Vellore. He pioneered community-based vaccination against diseases like polio, and I had the great fortune to meet him when I was an undergraduate. He allowed me to work in the virology laboratories at night and in the early mornings, outside my lectures. I learned how to ask scientific questions and define experiments, and was able to publish several papers on herpesvirus infections in India. Most importantly, this experience fired up my desire to focus seriously on research.There are many, many people across the developing world who have the potential to contribute to science, but are never able to realise it, not because they lack talent, but because they lack opportunity. As one of the fortunate few, giving back what I can has motivated me for many years.Throughout your career you have continued to support research in India. Why is this an important endeavour to you?Put simply, ‘There but for the grace of God’, has run through my mind throughout my career. When I was working in India decades ago, it was not easy for someone like me, with no formal research training or a PhD at that stage, to find the right opportunities and environment to become a better researcher or to get access to cutting-edge technologies. I was helped by the generosity of Gilbert Lenoir, who at that time was the head of one of the divisions of the World Health Organization (WHO)’s International Agency for Research on Cancer in Lyon, in France. Gilbert helped me, while I was still a medical student in India, to get WHO funding, which allowed me to work in France for several months and in Bristol for a month or two, where I met inspirational researchers like Tony Epstein and Alan Rickinson. During this time, I was also able to visit Marc Feldman, a leading immunology researcher in London. After we met, Marc offered me the opportunity to do a PhD in his lab. So, Gilbert's generosity opened doors, which enabled me to better fulfil what potential I had. There are many, many people across the developing world who have the potential to contribute to science, but are never able to realise it, not because they lack talent, but because they lack opportunity. As one of the fortunate few, giving back what I can has motivated me for many years. More recently, my journey has taken me to Singapore, a highly developed nation at the heart of Asia, which I believe has the talent, infrastructure and potential to be a beacon for biomedical research.You've made seminal discoveries in your career, but what discovery or research project have you found most exciting to work on?I'm afraid that I will have to give you more than one example! I have been excited by so many projects.The first example comes from the problem I initially worked on in my independent lab at the MRC LMB in Cambridge, after my postdoctoral work with Michael Neuberger. The adaptive immune response is initiated by specific, yet diverse, antigen receptors seated on the surface of B and T lymphocytes. Antigen receptor diversification is driven at the DNA level by the rearrangement of V, D and J segments distributed across large genomic regions. How does the enzymatic machinery executing rearrangement access such extensive genomic landscapes? We discovered that a cytokine receptor, the interleukin (IL)-7 receptor, which has a critical role in early lymphopoiesis, transmitted a signal to ‘open up’ the accessibility of the antibody heavy chain gene locus to cutting and repair by the rearrangement enzymes, RAG1 and RAG2 (Corcoran et al., 1998). This mechanism was later shown by Mark Schlissel and others to work for T-cell receptor gene loci, too. Therefore, our work raised the idea that antibody diversity was influenced by extrinsic signals, independent of antigen, early during lymphocyte development. As the first significant discovery from my independent lab, it's been exciting to see later implications of this work in the recent use of IL-7 for the therapy of cancer and immunodeficiency syndromes.Soon afterwards, our work on V, D and J segment rearrangement in the genome of immune cells took a wholly unexpected twist! I had been aware that the abnormal cutting and pasting of large genomic segments could generate the chromosomal instability that is near-universally prevalent in cancer cells from epithelial malignancies, but never thought that my work would switch towards understanding their genesis. What made the connection was a series of fortuitous events.Around that time, the breast cancer genes BRCA1 and BRCA2 had just been cloned, through large transnational collaborations led by Mary-Claire King and Michael Stratton, to identify the genetic defect in women with a high risk of developing familial breast and ovarian cancer. There was emerging evidence from Alan Bradley, Alan Ashworth and Tak Mak to suggest that cells lacking BRCA2 were sensitive to sources of DNA damage, like X-rays.Genes involved in V(D)J rearrangement in the immune system are known to be required for the repair of X-ray-induced DNA breaks. So, in our lab, I made the hypothesis that BRCA1 and BRCA2 might participate in double-strand DNA break repair and thereby be involved in V(D)J rearrangement. I approached Bruce Ponder and Martin Evans, who had created a BRCA2 knockout murine strain, for material to test this idea. However, part of the idea – namely, that BRCA2 might regulate V(D)J rearrangement – was soon shot down when Ann Corcoran, then a postdoc in my lab, showed that lymphocytes from the knockout mice exhibited no such defect. Nevertheless, Ketan Patel, who was also then a postdoc in my lab, and Veronica Yu, then my PhD student, found that fibroblasts from the BRCA2 knockout mice had growth and cell-cycle defects, plus a spectrum of sensitivities to DNA-break-inducing genotoxins, that together pointed to the involvement of BRCA2 in double-strand DNA break repair. Our work culminated in the demonstration that chromosomes from BRCA2-deficient cells spontaneously acquired breaks and formed abnormal structures termed ‘radial chromosomes’ when dividing in cell culture. Breaks affecting just one of the two sister chromatids, as well as tri-radial and quadri-radial chromosomes, were abundant, reflecting defects in mitotic recombination. Interestingly, these chromosomal lesions were quite similar to those that have been observed in other genetic diseases that predispose to cancer, such as Bloom syndrome and Fanconi anaemia. So, our findings collectively provided evidence to implicate BRCA2 in homology-directed DNA recombination between mitotic chromosomes. They also suggested that the pathogenesis of BRCA2-deficient tumours might recapitulate features of carcinogenesis associated with Bloom syndrome and Fanconi anaemia. Of course, it's been very satisfying to see that both of those early predictions have turned out to be correct! BRCA2 is indeed a central player in homology-directed DNA recombination (e.g. Moynahan et al., 2001), and our later work has gone on to help elucidate its mechanism (e.g. Pellegrini et al., 2002). Moreover, rare bi-allelic mutations in BRCA2 can give rise to Fanconi anaemia (Howlett et al., 2002).Despite our increasingly precise knowledge of how BRCA2 works at the molecular level, we still do not fully understand how patients carrying BRCA2 mutations develop cancer. Given my medical training, I suppose it has been natural for my lab to gravitate towards this problem, in work that continues to this day. I'll cite one last example of this work, which, in retrospect, has perhaps been the most difficult and most exciting problem we've taken on.Patients at a high risk from familial breast and ovarian cancer typically inherit one mutant and one normal (‘wild-type’) copy of BRCA2. As long as one wild-type copy of BRCA2 remains, cells seem to be pretty normal in their capacity to carry out the cancer-preventing functions of BRCA2 that preserve genome stability. Indeed, Al Knudson in the 1970s had proposed that both copies of tumour-preventing genes like BRCA2 must be inactivated to initiate carcinogenesis. This idea – called the Knudson ‘two-hit’ paradigm – has dominated contemporary thinking about the role of cancer-preventing genes, or ‘tumour suppressors’. Also, whether both copies of BRCA2 are inactivated in cancers from mutation carriers is proving to be quite important because sensitivity to targeted therapies, like platinum compounds or poly-ADP ribose polymerase (PARP) inhibitors, only occurs when that second wild-type copy of BRCA2 is lost. So, we developed the first model in the mouse germline that faithfully recapitulated features of BRCA2-dependent carcinogenesis. We chose to work on BRCA2-associated pancreatic cancer, not only because BRCA2 mutation carriers have higher susceptibility to this disease, but also because we could leverage earlier work by Dave Tuveson and Tyler Jacks, in order to create a new model for familial pancreatic cancer in my lab.Our first results were unexpected! Ferdinandos Skoulidis, at that time an MD, PhD student in my lab, working with Liam Cassidy, also then my PhD student, found that inactivation of a single copy of BRCA2 was sufficient to accelerate pancreatic carcinogenesis in our new model…but the tumours retained an intact second copy, which was still expressed normally, and remained resistant to PARP inhibitors. To my later chagrin, I did not believe these early results could be correct, and asked Ferdinandos and Liam to back up their observations with increasingly detailed experiments on more and more tumour samples, all of which supported their initial findings. We were fortunate enough to get a few precious samples of pancreatic cancer tissue from the Icelandic Cancer Registry, from carriers of a founder mutation in BRCA2 that is quite common in Iceland, and were able to validate our findings. So, BRCA2, at least in our model, can violate the Knudson two-hit paradigm (Skoulidis et al., 2010). Later data from The Cancer Genome Atlas project, and from Susan Domchek and Kate Nathanson's work, also supported this notion.Our quest to understand what was going on has led us in exciting new directions. Individuals even in families carrying the same germline BRCA2 mutation exhibit differences in their age of cancer onset and the type of cancers they may develop, speaking to the existence of modifiers of cancer risk. A few years ago, my lab identified a potential gene–environment interaction that could modify carcinogenesis in BRCA2 mutation carriers. As I've said cells from BRCA2 mutation carriers typically of the normal of BRCA2 because one of the two copies of the BRCA2 gene is Nevertheless, this of BRCA2 to be sufficient for cancer-preventing So, what these cells more to We found that when cells carrying a single copy of BRCA2 are with small of a class of BRCA2 is by what our evidence may be a but et al., When this we found that these cells the functions of BRCA2 in DNA repair. So, our findings the idea that – by BRCA2 – might normal cells carrying a single copy of BRCA2 towards like are in our and also by many important In early in carcinogenesis as cancer cells switch from by to by This termed is a of cancer. In work earlier this et al., we have been able to that an of can BRCA2 by of mutations that are in cancer Interestingly, we found that pancreatic cancer cells from the murine model we created to first that BRCA2 could violate two-hit paradigm also high of and similar of the from where we one idea that our recent findings is that in cancer or that during can two-hit for BRCA2, mutation in carcinogenesis. of paradigm in this might a mechanism by cancer cells to tumour mechanisms – and not just those by BRCA2. 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How can one lab work at that the and you have the a can do these in not to I me for a on to across the world is highly the one in we of of to small of patients with the very the other in you have people of diseases for which is no in their of not no to level this but I do that access to drug discovery has to become more We to access to new in so they can work on that may not be at the of in or the for was one for me to the Centre for Biology and in India, with help many years from the of the Sciences and support from the of of India. We had the that the and will be working with us in to help to develop new for the of the many than the very excited about these new the Director of the Cancer Science at Institute of Singapore. How was the move and how is it your the time of my – great science, and by the Singapore into biomedical research and its I've been very excited to move to Singapore after more than years in the and response to therapy of many including cancer. of the is of genetic of what we about cancer comes from and samples that European genetic So, I believe that the Cancer Science to understand the pathogenesis of cancers prevalent in Asia, and use this new knowledge to clinical is and important not only to Asia, but also to our across the common of cancer in like cancer, also of cancer at higher in than in such as or breast cancer, or cancer in cancers in or like these cancers a of scientific of to that also mechanisms of a my move has been to into in this is of and reflecting large across Singapore has very on the between genetic diversity and disease, with infrastructure as for genomic to this In this one and so it's easy to find and to and in or So, it's been easy to down after my of the is of genetic of what we about cancer comes from and samples that European genetic do you outside of the lab and have outside of research, and I've been able to a few of after the in through the of the great like and others that have from and my move to Singapore, my experience was to India, and a few of and it's easy to visit across and the of from India and from how that has led to so many like has been one of the I've most after my also quite and I've been able to in the in and are a of in or an in the other one of my in the is to I my few will just have to Ashok Venkitaraman for his to be and for his and with Ashok was by for and this has been and with the