CIZ1 is overexpressed breast, lung, prostate, colon cancers that constitute >50% of cancer incidence in the NWCR region. CIZ1 regulates the G1/S transition, and initiation of DNA replication. The deregulation of the cell cycle promotes DNA replication stress (DRS) through premature S-phase entry, increase replication initiation or origin firing and alters replication fork rates. Our preliminary data have established that CIZ1-/- increases DRS and modifies the CDK activity threshold for initiation of DNA replication. Our hypothesis is that CIZ1 levels contribute to the maintenance of genome stability through regulation of the DNA replication machinery. This project aims to determine how CIZ1 contributes to genome stability by functional characterisation of its role in DRS. This proposal will interrogate the alterations at the replisome assembly, replication fork kinetics and responses to induced DRS in CIZ1 null cell lines to gain greater insight into the role of CIZ1 at the replication fork.
Understanding how CIZ1 contributes to genomic stability and recovery from DNA replication stress is vital for developing strategies to reduce tumour growth in CIZ1 dependent tumours.
Cancer develops in response to increases in changes to our genetic code - DNA. These changes can be caused by exposure to chemicals that damage DNA such as in smoking or through mutations that happen when our DNA is copied. Normally our DNA is copied with extremely highly levels of accuracy making an around 1 mistake per billion bases copied. This ensures a long an healthy life. However, sometimes there are changes in proteins that cause stress during the copying of our genetic code as cells divide that can lead to increases in the rate of mutation. This project aimed to see how a single gene (CIZ1) contributes to genetic stability by removing it from cells and looking to see if the cells are more "stressed" in its absence. This project aims to uncover how this gene contributes to protection of DNA from mutation and also how it is linked to cancer. It is hoped that understanding these events could lead to new approaches to treating cancer.
