DDR-MYCN-NB · The DNA damage response pathway in MYCN amplified neuroblastoma

Accurate replication of the genome is very important in cells to prevent the propagation of mutations which cause tumour development. After DNA damage, normal non-cancerous cells arrest the cell cycle in G1 to prevent cell growth until DNA damage is repaired or, if levels of damage are high, cells undergo programmed cell death. Stress responses leading to a DNA damage response stem from different sources and activate distinct pathways. However, they converge on the same components of the cell cycle machinery in the G1 phase of the cell cycle, namely the cyclin dependent kinases. To investigate the mechanisms that MYC proteins affect the G1 checkpoint, we propose to use neuroblastoma with deregulated MYCN expression as a paradigm to examine the mechanisms that MYC proteins act on the DNA damage response pathway. This DNA damage pathway is complex and acts in two main stages, an early inhibition of cyclin dependent kinase inhibitors by redistribution of p21WAF1 and a more sustained transcriptional response is mediated by p53. To appreciate the complexity of the DNA damage response pathway experimental data will be integrated with computer based mathematical modelling techniques to build a model of this pathway and how it is affected by deregulated MYCN expression. Understanding the effect of MYC proteins on the DNA damage pathway is essential for future advances in cancer treatments, as a large number of current chemotherapeutics are DNA damaging agents. This project will provide a general model for all cancer types driven by MYC proteins, it will also provide important prognostic indicators and new drug targets for the treatment of neuroblastoma- a cancer that accounts for 8% of all childhood malignancies where patients diagnosed with high risk neuroblastoma have a 5-year overall survival of only ~60%.""