Ashok Venkitaraman

Last updated

Ashok Venkitaraman
Alma mater
Awards
Website https://www.csi.nus.edu.sg/web/ashok-venkitaraman/ https://www.mrc-cu.cam.ac.uk/research/ashok-venkitaraman-folder
Academic career
FieldsImmunology, Oncology, Molecular biology, Chemical biology
InstitutionsCancer Science Institute of Singapore

National University of Singapore A*STAR Singapore

Medical Research Council (MRC) Cancer Unit University of Cambridge

Contents

MRC Laboratory of Molecular Biology
Thesis The regulation of MHC class 2 gene expression by tumours of the B lymphocyte lineage
Doctoral advisor Marc Feldmann

Ashok Venkitaraman is a British cancer researcher of Indian origin. He is the Director of the Cancer Science Institute of Singapore, a Distinguished Professor of Medicine at the National University of Singapore, and Program Director at A*STAR, Singapore. [1] From 1998 to 2020, he was the inaugural holder of the Ursula Zoellner Professorship of Cancer Research at the University of Cambridge, a Professorial Fellow at Pembroke College, Cambridge, and from 2006 to 2019, was the Director of the Medical Research Council Cancer Unit [2] [3] [4]

Biography

Venkitaraman learnt and practiced medicine at the Christian Medical College, Vellore, India, before earning his PhD at University College London supervised by Sir Marc Feldman. [2] [5] [3] He was awarded in 1988 a Beit Memorial Fellowship to work with Michael Neuberger at the MRC Laboratory of Molecular Biology in Cambridge, before becoming a member of its research faculty in 1991. In 1998, he was elected as the first holder of the Ursula Zoellner Professorship [6]

Venkitaraman joined the MRC Cancer Unit in 2000, becoming its co-director with Ron Laskey in 2006, and its Director in 2010. During his directorship, he developed a distinctive scientific mission for the MRC Cancer Unit focused on early intervention in cancer, through research that advances understanding of early steps in carcinogenesis, and utilizes this new knowledge for the early detection of cancer, and improvements in therapy or prevention.

In 2020, Venkitaraman took up joint appointments as the Director of the Cancer Science Institute of Singapore, Distinguished Professor of Medicine at the National University of Singapore, and Program Director at A*STAR, Singapore.

Research

Venkitaraman is widely recognised for his contributions to understanding the genetics and biology of human cancer, particularly in elucidating the impact of genome instability on carcinogenesis and cancer therapy. He is best known for discovering how mutations affecting the breast cancer gene, BRCA2, and related proteins cause genome instability to trigger carcinogenesis. [7] [8] His work has helped to explain why carriers of BRCA2 mutations develop cancer, [7] [8] and has provided the scientific foundations for new cancer therapies by illuminating fundamental cellular mechanisms that control genome repair, duplication and segregation. [7] [8]

Venkitaraman was amongst the first to discover that the breast cancer gene, BRCA2, is essential to maintain the integrity of the genome when cells divide. [9] He and his colleagues soon uncovered that BRCA2 enables cells to repair DNA breakage in an error-free manner by precisely controlling the assembly of the RAD51 recombination enzyme on its DNA substrates, [9] [10] [11] and revealed the structural mechanism underlying this process. [9] [12] He subsequently discovered that BRCA2 is vital to prevent DNA breakage when genome replication becomes blocked or stalled, [13] helping to explain why BRCA2-deficient cells spontaneously exhibit genome instability during cell division, and why BRCA2-deficient cancers become highly sensitive to drugs that block genome replication by causing DNA cross-links or gaps. [8] These discoveries have laid a scientific foundation for the development of new treatments for cancers arising in patients who carry BRCA2 mutations, and also provided a conceptual framework for understanding other human genetic diseases in which genome instability is connected with predisposition to cancer. [8]

Venkitaraman's research continues to unveil new ways in which BRCA2 and related genes work to preserve genome integrity, and to explain how patients who carry BRCA2 mutations become more susceptible to early-onset cancers. He and his colleagues have recently discovered that cells carrying a single copy of mutant BRCA2 become more susceptible to the mutagenic effects of aldehydes, a class of chemicals found pervasively in the environment and generated in cells through metabolic reactions. [14]

Venkitaraman has developed technologies that help to identify and validate new targets for next-generation medicines against cancer and other diseases. Work in his laboratory laid the scientific foundations for the development of “protein interference” at PhoreMost, [15] which he co-founded with Chris Torrance and Grahame Mckenzie. This new technology is now being widely applied in collaborations with major pharmaceutical companies. [16] [17] Venkitaraman's laboratory has also devised new approaches to target cellular pathways initiated by enzymes like protein kinases. For example, they have selectively interrupted intracellular signaling by blocking the molecular recognition of protein phosphorylation using small-molecule chemical tools, [18] now being pursued by industry for anti-cancer therapy. He has worked extensively with UK industry to develop new medicines. Having served for many years on the scientific advisory boards of companies such as Astex Therapeutics and Cambridge Antibody Technology/MedImmune, he currently holds appointments with Sentinel Oncology and PhoreMost.

Venkitaraman has worked for many years to promote biomedical research in India. He leads a collaborative research initiative with the National Center for Biological Sciences and inStem in Bangalore, [19] [20] in which new technology is being applied to help develop drugs against cancer and other diseases. He has established an initiative for biological systems engineering at the Indian Institute of Technology-Madras, where he holds the Mehta Foundation Visiting Professorship.

Awards and honours

Related Research Articles

<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

<span class="mw-page-title-main">Microsatellite instability</span> Condition of genetic hypermutability

Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR). The presence of MSI represents phenotypic evidence that MMR is not functioning normally.

<span class="mw-page-title-main">Oncogenomics</span> Sub-field of genomics

Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.

<span class="mw-page-title-main">RAD51</span>

DNA repair protein RAD51 homolog 1 is a protein encoded by the gene RAD51. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA, Archaeal RadA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.

<span class="mw-page-title-main">MSH6</span> Protein-coding gene in the species Homo sapiens

MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6. The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.

<span class="mw-page-title-main">CHEK2</span> Protein-coding gene in humans

CHEK2 is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.

<span class="mw-page-title-main">BARD1</span> Protein-coding gene in the species Homo sapiens

BRCA1-associated RING domain protein 1 is a protein that in humans is encoded by the BARD1 gene. The human BARD1 protein is 777 amino acids long and contains a RING finger domain, four ankyrin repeats, and two tandem BRCT domains.

<span class="mw-page-title-main">FANCD2</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN and FANCO.

<span class="mw-page-title-main">BRIP1</span> Mammalian protein found in Homo sapiens

Fanconi anemia group J protein is a protein that in humans is encoded by the BRCA1-interacting protein 1 (BRIP1) gene.

<span class="mw-page-title-main">HMG20B</span> Protein-coding gene in the species Homo sapiens

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1-related is a protein that in humans is encoded by the HMG20B gene.

Somatic evolution is the accumulation of mutations and epimutations in somatic cells during a lifetime, and the effects of those mutations and epimutations on the fitness of those cells. This evolutionary process has first been shown by the studies of Bert Vogelstein in colon cancer. Somatic evolution is important in the process of aging as well as the development of some diseases, including cancer.

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death, whereas a deficiency of only one of these genes does not. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differing phenotype, and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

<span class="mw-page-title-main">Ketan J. Patel</span>

Ketan Jayakrishna Patel is a British-Kenyan scientist who is Director of the MRC Weatherall Institute of Molecular Medicine and the MRC Molecular Haematology Unit at the University of Oxford. Until 2020 he was a tenured principal investigator at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB).

<span class="mw-page-title-main">Jórunn Erla Eyfjörð</span> Icelandic academic

Jórunn Erla Eyfjörð is an Icelandic molecular biologist and professor emerita at the Faculty of Medicine of the University of Iceland. She is known for her research on breast cancer genetics.

References

  1. ↑ "Prominent cancer researcher Ashok Venkitaraman to head Cancer Science Institute of Singapore at NUS".
  2. 1 2 "MRC Cancer Unit Professor Ashok Venkitaraman biography".
  3. 1 2 "Venkitaraman, Prof. Ashok. UK WHOS WHO. 2017". doi:10.1093/ww/9780199540884.013.41050. ISBN   978-0-19-954088-4.
  4. ↑ "Fellows and College Officers, Pembroke College Cambridge".
  5. ↑ Venkitaraman, Ashok Ramakrishnan (1989). Venkitaraman, Ashok (1989). "The regulation of MHC class 2 gene expression by tumours of the B lymphocyte lineage" (Ph.D).
  6. ↑ "University of Cambridge Reporter University Officers".
  7. 1 2 3 Venkitaraman, A. R. (January 2002). "Cancer Susceptibility and the Functions of BRCA1 and BRCA2". Cell. 108 (2): 171–182. doi: 10.1016/s0092-8674(02)00615-3 . PMID   11832208. S2CID   10397442.
  8. 1 2 3 4 5 Venkitaraman, A. R. (27 March 2014). "Cancer Suppression by the Chromosome Custodians, BRCA1 and BRCA2". Science. 343 (6178): 1470–1475. Bibcode:2014Sci...343.1470V. doi:10.1126/science.1252230. PMID   24675954. S2CID   206556058.
  9. 1 2 3 Patel, K. J.; Yu, V. P. C. C.; Lee, H.; Corcoran, A.; Thistlethwaite, F. C.; Evans, M. J.; Colledge, W. H.; Friedman, L. S.; Ponder, B. A. J.; Venkitaraman, A. R. (February 1998). "Involvement of Brca2 in DNA Repair". Molecular Cell. 1 (3): 347–357. doi: 10.1016/s1097-2765(00)80035-0 . PMID   9660919.
  10. ↑ "The Fight Against Cancer - University of Cambridge news story".
  11. ↑ Shivji, M. K. K.; Mukund, S. R.; Rajendra, E.; Chen, S.; Short, J. M.; Savill, J.; Klenerman, D.; Venkitaraman, A. R. (23 July 2009). "The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange". Proceedings of the National Academy of Sciences. 106 (32): 13254–13259. Bibcode:2009PNAS..10613254S. doi: 10.1073/pnas.0906208106 . PMC   2714763 . PMID   19628690.
  12. ↑ Short, J. M.; Liu, Y.; Chen, S.; Soni, N.; Madhusudhan, M. S.; Shivji, M. K. K.; Venkitaraman, A. R. (5 September 2016). "High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy". Nucleic Acids Research. 44 (19): 9017–9030. doi:10.1093/nar/gkw783. PMC   5100573 . PMID   27596592.
  13. ↑ Lomonosov, M.; Anand, S.; Sangrithi, M.; Davies, R.; Venkitaraman, A. R. (15 December 2003). "Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein". Genes & Development. 17 (24): 3017–22. doi:10.1101/gad.279003. PMC   305253 . PMID   14681210.
  14. ↑ Tan, S. L. W.; Chadha, S.; Liu, Y.; Gabasova, E.; Perera, D.; Ahmed, K.; Constantinou, S.; Renaudin, X.; Lee, M.; Aebersold, R.; Venkitaraman, A. R. (June 2017). "A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability". Cell. 169 (6): 1105–1118.e15. doi:10.1016/j.cell.2017.05.010. PMC   5457488 . PMID   28575672.
  15. ↑ "Cambridge University Enterprise announcement".
  16. ↑ "PhoreMost and Boehringer Ingelheim enter multi-project drug discovery collaboration - Drug Discovery Today". www.drugdiscoverytoday.com.
  17. ↑ "Otsuka enters multi-project drug discovery collaboration with PhoreMost Limited｜News Releases". Otsuka Pharmaceutical Co., Ltd.
  18. ↑ Narvaez, A. J.; Ber, S.; Crooks, A.; Emery, A.; Hardwick, B.; Guarino Almeida, E.; Huggins, D. J.; Perera, D.; Roberts-Thomson, M.; Azzarelli, R.; Hood, F. E.; Prior, I. A.; Walker, D. W.; Boyce, R.; Boyle, R. G.; Barker, S. P.; Torrance, C. J.; McKenzie, G. J.; Venkitaraman, A. R. (August 2017). "Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS". Cell Chemical Biology. 24 (8): 1017–1028.e7. doi:10.1016/j.chembiol.2017.07.009. PMC   5563081 . PMID   28807782.
  19. ↑ "Department of Biotechnology, Cambridge varsity in research venture". @businessline. 14 September 2012.
  20. ↑ "Breakthrough medical research collaboration receives Indian government funding boost". University of Cambridge. 5 October 2012.
  21. ↑ "Penn's Basser Center for BRCA Names Cambridge Cancer Researcher Ashok Venkitaraman Winner of 2017 Basser Global Prize".
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