Basic Science > Maintenance of Genome Stability

Our research groups include Carlos Rubbi and Nikolina Vlatkovic and we are funded by Cancer Research UK, the MRC and Mersey Kidney Research to investigate several aspects of the process of cancer development and progression including mechanisms regulating genomic stability.

We have excellent local collaborations with the Clatterbridge Research Group (Sibson), the Biomarkers group (Liloglou), the Head and Neck Cancer clinical research teams (led by Jones and Shaw). We are also collaborating externally with a number of groups and have relatively new ones with scientists at the Paterson Institute (Malliri), in Oxford (Kelsh), the Karolinska (Selivanova) and in Hannover (Kotlyarov) and with SibTech Inc. in the USA.

We have projects focussing on disease progression in renal cancer (clear cell renal carcinoma) and are also investigating the functional consequences of molecular alterations in squamous cell carcinomas of the head and neck. As part of our investigation of p53-mediated responses the group is investigating the cellular response (cell cycle arrest, DNA repair, apoptosis, senescence) to genotoxic stresses with a particular focus on the p53/MDM2 axis. Biochemically these cellular responses are regulated by a range of post-translational modifications and these are themselves under the control of higher order regulation through sub-cellular compartmentalisation. A novel MDM2 binding protein (MTBP) that inhibits MDM2 ubiquitination was identified by us and we have also discovered that p53 activation can be controlled by the nucleolus (Rubbi). Recent work has identified a p53-independent activity of MDM2 that modulates sensitivity to chemotherapeutic drugs and has consequences for cellular one-carbon metabolism, with implications for global control of methylation.

We are interested in how cells prioritise one stress response over another and this question is being approached at three levels: at the cellular level by studying subcellular compartmentalisation of response pathways; at the histological level by studying changes in cell motility/invasiveness and at the genetic level by translating our biochemical findings into transgenic models. This understanding of the cellular responses to genotoxic stresses is being applied to the identification of new and better targets for therapy. For example, our studies suggest that organelle function (ribosomal biogenesis/nucleolar transport) can translate genotoxic stress into p53 activation, therefore defining a host of new potential targets for therapeutic intervention. Taking advantage of the clinical expertise and resources this basic research is being translated in to clinically relevant settings particularly in renal cancer and in head and neck cancer.

Groups specialising in this field:
Dr Mark Boyd		Dr Nikolina Vlatkovic		Dr Carlos Rubbi