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Ashok Venkitaraman


Understanding chromosomal instability and exploiting it for cancer therapy

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Chromosomal aberrations (top) occur when pathways for DNA recombination (bottom) are defective.

Chromosomal aberrations (top) occur when pathways for DNA recombination (bottom) are defective.

Top panel from Patel, et al. (1998) Mol Cell 1, 347-357.
Bottom panel from Venkitaraman (2003) N Engl J Med 348, 1917-1919.

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Cancer is expected to 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 millions 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 events that lead to carcinogenesis. To do this, we study human genetic diseases in which the instability of chromosome structure or number is linked with predisposition to common types of cancer. Our focus is on understanding the biological mechanisms that are relevant to disease pathogenesis, using a range of techniques from molecular cell biology to interventional microscopy to structural biology and biophysics. This approach has led us to develop new experimental tools with wide application, and to a broad range of research interests in 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.

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 signalling 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 in 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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AURORA-A over-expression, which occurs in 30-50% of common cancers.

AURORA-A over-expression, which occurs in 30-50% of common cancers, over-rides the mitotic spindle assembly checkpoint mediated by MAD2, allowing anaphase entry with lagging chromosomes. Aurora-A over-expressing cells (right) or control cells (left) in prometaphase (top) or anaphase (bottom). DNA is stained red and MAD2, green.

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Model for BRCA2 function.

Structure of a complex (top) between RAD51 (magenta/blue) and BRCA2 (green) predicts their possible functions in DNA recombination (bottom, from Venkitaraman (2002) Cell 108, 171-182).

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Click here to contact Professor Ashok Venkitaraman by email.


Recent Publications

Continuous polo-like kinase 1 activity regulates diffusion to maintain centrosome self-organization during mitosis. Mahen R, Jeyasekharan AD, Barry NP, Venkitaraman AR. Proc Natl Acad Sci USA. 2011 May 31;108(22):9310-5.

Germline Brca2 heterozygosity promotes Kras(G12D) –driven carcinogenesis in a murine model of familial pancreatic cancer. Skoulidis F, Cassidy LD, Pisupati V, Jonasson JG, Bjarnason H, Eyfjord JE, Karreth FA, Lim M, Barber LM, Clatworthy SA, Davies SE, Olive KP, Tuveson DA, Venkitaraman AR. Cancer Cell. 2010 Nov 16;18(5):499-509.

UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J, Russell P, Pines J, Venkitaraman AR. Nat Cell Biol. 2009 Nov;11(11):1363-9. Epub 2009 Oct 11.

HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR.
Nature. 2008 May 29;453(7195):682-6. Epub 2008 Apr 27.


To undertake world leading research into cancer cell biology that can be translated into clinical practice to improve the diagnosis and treatment of cancers.