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 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.

Figure 1: Chromosomal aberrations (left panel) occur when pathways for DNA recombination (right panel) are defective. Right panel is from Venkitaraman (2003) N Eng J Med 348:1917

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.

Figure 2: 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.

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.

Figure 3: Structure of a complex (left panel) between RAD51 (magenta/blue) and BRCA2 (green) predicts their possible functions in DNA recombination (right panel, from Venkitaraman (2002) Cell 108:171).

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.