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Ashok Venkitaraman
Chromosomal instability and cancer: Translating molecular insights to clinical practice
Human cancer cells almost always contain abnormal chromosomes, yet the connections between chromosomal instability and carcinogenesis are poorly understood. We aim not only to understand how cells maintain normal chromosome structure and number, and why maintenance should break down in cancer cells, but also to translate this knowledge to improvements in cancer diagnosis and treatment.
Our work spans three broad themes. Many genes whose inactivation predisposes to cancer work in pathways for DNA replication and recombination, which monitor and repair DNA lesions during the S phase of the cell cycle. We study these pathways to understand how their inactivation causes human genetic diseases - including inherited breast cancer susceptibility, Bloom syndrome and Fanconi anaemia - in which chromosomal instability triggers cancer predisposition.
Cell cycle checkpoints during G2 and M phases work together with replication/recombination pathways in preserving chromosome integrity, and are the targets for cancer drugs like Taxol. We study these checkpoints to understand how checkpoint dysfunction contributes to cancer progression and drug resistance.
We actively translate molecular insights from our studies to clinical practice. New therapeutic approaches are emerging from studies on the DNA replication/recombination and G2/M checkpoint pathways. Markers that predict the effectiveness of cancer therapies like Taxol are being identified, based on insight into G2/M checkpoints.
We focus on questions rather than techniques, employing a wide range of approaches from molecular cell biology and somatic cell genetics, to structural biology and biophysics.
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Chromosomal aberrations (top) occur when pathways for DNA recombination (bottom) are defective.
Top panel is from Patel, et al. (1998) Mol Cell 1, 347-357. PubMed
Bottom panel is from Venkitaraman (2003) N Engl J Med 348, 1917-1919.PubMed
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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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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). PubMed
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- Daniels, M.J., Marson, A and Venkitaraman, A.R (2004)
PML bodies control the nuclear dynamics and function of the CHFR mitotic checkpoint protein.
Nature Structural & Molecular Biology, 11, 1114-21
- Daniels, M.J., Wang, Y., Lee, M and Venkitaraman, A.R (2004)
Abnormal Cytokinesis in Cells Deficient in the Breast Cancer Susceptibility Protein BRCA2
Science 306, 876-879
- Yu, D.S., Sonoda, E., Takeda, S., Huang, C.L.H., Pellegrini, L., Blundell, T.L. and Venkitaraman, A.R. (2003)
Dynamic control of RAD51 in the nucleus of living cells by self-association and interaction with BRCA2.
Mol Cell 12, 1029-1041.
- Anand, S., Penrhyn-Lowe, S., and Venkitaraman, A.R. (2003)
AURORA-A amplification over-rides the mitotic spindle assembly checkpoint, inducing resistance to Taxol.
Cancer Cell 3, 51-62.
- Pellegrini, L., Yu, D.S., Lo, T., Anand, S., Lee, M. Blundell, T.L., and Venkitaraman, A.R. (2002)
Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.
Nature 420, 287-294.
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