Defining how defects in actin-dependent DNA repair and replication cause disease

Radiotherapy works by inducing irreparable damage into the DNA of tumour cells, which triggers them to die. Significant advances in radiotherapy have been made towards being able to specifically target a tumour with radiation whilst reducing the harmful effects on the surrounding normal tissue. Nevertheless, there are a growing number of genetic factors being identified that influence the effectiveness of the radiotherapy or even prevent its use as an anti-cancer treatment altogether. One of these genetic factors is an inherited hypersensitivity to radiation, which is caused by mutations in specific genes involved in repairing radiation-induced DNA damage. Often, individuals that have inherited mutations in DNA repair genes are highly prone towards developing tumours. However, since every cell in the affected individual’s body is exquisitely sensitive to radiation, the unrepaired DNA damage induced by the radiotherapy would trigger life-threatening amounts of cell death. Consequently, it is imperative to identify tumour-prone patients who have an inherited genetic defect that compromises the repair of DNA damage-induced by radiation, such that alternative treatments can be used to prevent unforeseen therapy-related death. Several rare, cancer-prone syndromes are known to be caused by mutations in specific DNA repair genes e.g. Ataxia-Telangiectasia or Nijmegen Breakage Syndrome. However, affected individuals are usually identified before cancers develop due to the presence of other clinical symptoms, such as small head/brain, dwarfism, recurrent infections or problems with balance/walking. Thus, if cancer develops in these individuals then radiotherapy is avoided. Despite this, new DNA repair genes are constantly being identified. However, whether they are linked to human disease and cancer development or cause a life-threatening sensitivity to radiotherapy if mutated is unknown. In this respect, we have identified a new DNA repair gene called DIAPH1, that is mutated in a previously undiscovered syndrome associated with cancer development and an increased sensitivity to radiation. The function of DIAPH1 is to aid the formation of actin chains in the cell, which are usually important for controlling cell size, shape, movement and division. However, our preliminary data would suggest that DIAPH1 and actin are also important for repairing DNA damage, but how this occurs is not understood. Based on this, the focus of this project is to understand how DIAPH1 and actin control DNA repair with the aim of identifying cellular defects that may contribute to the development of disease. This will be achieved via three main objectives: Investigate how loss/mutation of DIAPH1 affects the capacity of cells to repair DNA damage induced by radiation. Investigate whether DIAPH1-dependent DNA repair is linked with its ability to promote the formation of actin chains. Investigate whether loss/mutation of DIAPH1 and actin also increases the sensitivity of cells to chemotherapeutic agents that block the ability of cells to copy their DNA. The overall outcome of this project is to define the cellular defects arising from loss/mutation of DIAPH1 to allow better clinical management of disease and to prevent adverse side effects associated with treating affected patients that develop a tumour with radio/chemotherapy.