Professor Ashok Venkitaraman
Director, MRC Cancer Unit
The Ursula Zoellner Professor of Cancer Research
Chomosomal instability in cancer pathogenesis and treatment
Cancer will affect 1 in every 3 people at some stage in their lives, making it a frequent cause of illness and death in every country in the world. Yet, looked at from a different perspective, one might as well ask, 'Why is cancer so rare?' instead of 'Why is cancer so common?' The human body comprises many trillions of cells, any one of which could potentially accumulate genetic alterations that lead to carcinogenesis. That this seldom occurs is testament to the efficiency of a network of cellular machines that preserve the integrity of the human genome, particularly during cell division
We study this network not only to understand its physiology, but also to better define the earliest events that lead to cancer. One major interest is in exploring human genetic diseases in which the instability of chromosome structure or number is linked with predisposition to common types of cancer. This is complemented by a range of fundamental studies on DNA repair, replication and mitosis relevant to genome stability and cancer. For example, we have defined functions of the breast cancer susceptibility protein BRCA2 in the repair of replication-associated DNA lesions by homologous recombination mediated by the enzyme RAD51, discovered a role in the initiation of DNA replication for the Rothmund-Thomson syndrome helicase, RECQL4, and demonstrated how frequent amplification of the Aurora-A kinase in human cancers mis-regulates the machinery for chromosome segregation.
Our focus is on understanding the biological mechanisms that are relevant to disease pathogenesis, and on exploiting this understanding in new approaches to the therapy of the commonest human cancers. Therefore, our research spans a wide range of techniques from molecular cell biology to single-cell/single-molecule imaging to structural biology, biophysics and chemistry.Our question-driven approach has led us to develop new experimental tools with wide application in several fields, and to a broad range of research interests relevant to genome stability and cancer. We have recently devised a general tool for conditional protein degradation in vertebrate cells, and used it to disable or reconstitute homologous recombination during different stages of the cell cycle, engendering a model in which homologous recombination during G2 is segregated from replication in S, and chromosome segregation, in M. We have combined biophysical microscopy with cell biology to identify a transient and rapid alteration in chromatin structure that precedes and permits phosphorylation of the variant histone, H2AX, defining a new signaling pathway that senses DNA breakage, and showing that chromatin structure can be changed during a physiological process via modification of a histone-code effector rather than the code itself.
One key goal of our work is to translate insights from fundamental research to improvements in the treatment of cancer. This has led to strong collaborations with colleagues in physics, chemistry and clinical medicine, besides pharma and biotech companies. We participate in the Cambridge Molecular Therapeutics Programme, a University-wide interdisciplinary initiative to pioneer approaches for the discovery and development of drugs against new types of molecular targets, as well as the Physics of Medicine programme.
These links support a range of ongoing projects in our laboratory that use interdisciplinary tools to investigate biological problems, and to create small molecules as tools for chemical biology and to seed the development of drugs.
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Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Venkitaraman, A.R. Science (2014) 343(6178):1470-5.
Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing. Liang H, Esposito A, De S, Ber S, Collin P, Surana U, Venkitaraman AR. Nature Commun (2014) 5:4048.
Diversity-oriented synthesis as a tool for identifying new modulators of mitosis. Ibbeson B.M., Laraia L., Alza E, O' Connor C.J., Tan Y., Davies H.M., McKenzie G., Venkitaraman A.R.*, Spring D.* Nature Commun. (2014) 5:3155.
A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Jeyasekharan, A.D., Liu, Y., Hattori, H., Pisupati, V., Jonsdottir, A.B., Rajendra, E., Lee, M., Sundaramoorthy, E., Schlachter, S., Kaminski, C., Rosenfeld, Y., Sato, K., Savill, J., Ayoub, N.& Venkitaraman, A.R. Nature Str Mol Biol. (2013). 20, 1191-8.
Human inositol polyphosphate kinase regulates transcript-selective nuclear mRNA export to preserve genome integrity.Wickramasinghe, V., Savill, J. Chavali, S., Jonsdottir, A.B., Rajendra, E., Gruner, T., Laskey, R., Babu, M., & Venkitaraman, A.R. (2013). Molecular Cell. 51, 737-43.
Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis. Mahen, R., Jeyasekharan, A.D., Barry, N.P., and Venkitaraman, A.R. Proc Natl Acad Sci (2011). USA 108, 9310-9315.
Germline BRCA2 heterozygosity promotes KrasG12D–driven carcinogenesis in a murine model of familial pancreatic cancer.Skoulidis, F., Cassidy, L., Pisupati, V., Jonasson, J., Eyfjord, J., Kerreth, F., Lim, M., Olive, K. Tuveson, D. & Venkitaraman, A. R. Cancer Cell (2010) 18, 499-509.
The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange. Shivji, M. K., Mukund, S. R., Rajendra, E., Chen, S., Short, J. M., Savill, J., Klenerman, D., and Venkitaraman, A. R. Proc Natl Acad Sci USA (2009). 106, 13254-13259
UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Garnett, M., Mansfeld, J., Godwin, C., Matsusaka, T., Wu, J., Russell, P., Pines, J. & Venkitaraman, A. R. Nature Cell Biol (2009). 11, 1363-69.
HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Ayoub N.A., A.D. Devaprasath, J.A. Bernal & A.R. Venkitaraman Nature (2008). 453: 682-6.