DNA damage response pathways play important roles in preventing the onset of cancer and regulating the clinical response to chemotherapeutics, and some of the relevant proteins have additional functions during normal development. This fellowship will study new a human protein with key roles in the formation of the lung, and its roles in preventing devastating consequences of normal oxidative damage to DNA, as well as additional fundamental mechanisms involved in preventing genome mutations.
Understanding the mechanisms in the development of mutations in cancers will assist in development of targeted therapies to overcome chemotherapy resistance. The recently discovered TMPRSS2:ERG fusion in prostate cancer is unique as dominant fusion translocations are uncommon in solid organ malignancy. Activation induced cytidine deaminase (AID) is thought to play a role. Understanding the role of AID and downstream DNA repair pathways may be a target for future therapies in cancer.
Functions Of ASCIZ In The Repair Of Accidental And Programmed DNA Base Damage
Funder
National Health and Medical Research Council
Funding Amount
$613,060.00
Summary
Every cell in the body encounters approximately 10,000 DNA base lesions per day. If not accurately repaired, this DNA damage may give rise to cancer. We have discovered a new protein called ASCIZ that is involved in the cellular response to base damage. We believe that ASCIZ functions by promoting the most efficient way to repair damaged DNA bases. We will investigate this hypothesis using cells that lack the ASCIZ gene, and also test if defective ASCIZ leads to increased cancer.
DNA Lesions Involved In Chemotherapy Responses And Their Repair
Funder
National Health and Medical Research Council
Funding Amount
$399,142.00
Summary
The integrity of the human genome is constantly threatened by spontaneous DNA damage from products of normal metabolism, for example DNA oxidation, or environmental mutagens and carcinogens such as UV light. Improperly repaired DNA damage is a major contributing factor to the onset of cancer. To prevent this, human cells have a multitude of specialised DNA repair mechanisms to repair distinct lesions in the best possible way. As a consequence, mutations in DNA repair genes lead to increased canc ....The integrity of the human genome is constantly threatened by spontaneous DNA damage from products of normal metabolism, for example DNA oxidation, or environmental mutagens and carcinogens such as UV light. Improperly repaired DNA damage is a major contributing factor to the onset of cancer. To prevent this, human cells have a multitude of specialised DNA repair mechanisms to repair distinct lesions in the best possible way. As a consequence, mutations in DNA repair genes lead to increased cancer risk. Common examples for cancer-associated DNA repair gene mutations include the BRCA1 and BRCA2 breast cancer genes, and the MLH1 gene mutated in familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a function similar to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in the cell nucleus. However, compared to BRCA1-BRCA2, ASCIZ performs this function in response to different types of DNA damage and acts in concert with the MLH1 protein. Here we want to investigate what the specific DNA lesions are that are repaired by ASCIZ, and we want to determine if the repair involves a copy mechanism that utilises intact genes as repair templates. In addition, we want to generate animals in which the ASCIZ gene is mutated, as a model to study its role in cancer development in humans. Cells that lack ASCIZ are dramatically hypersensitive to DNA damaging agents that are similar to clinically used chemotherapy drugs. We hope that our studies may identify possible approaches to develop drugs against ASCIZ and related proteins in order to kill cancer cells more efficiently.Read moreRead less
Regulation And Assembly Of Nuclear DNA Repair Centres
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Genetic defects in DNA repair genes are associated with increased cancer risk in humans. For example, BRCA1 and BRCA2 gene mutations are the most common causes of familial breast cancer, and MLH1 gene mutations are the most common cause of familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a similar function to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in ....Genetic defects in DNA repair genes are associated with increased cancer risk in humans. For example, BRCA1 and BRCA2 gene mutations are the most common causes of familial breast cancer, and MLH1 gene mutations are the most common cause of familial non-polyposis colorectal cancer. We have identified a novel human DNA repair protein termed ASCIZ that performs a similar function to BRCA1 and BRCA2 in that it regulates the concentration of the RAD51 repair protein in specific DNA repair centres in the cell nucleus. However, ASCIZ performs this function in response to different types of DNA damage than BRCA1-BRCA2, and it acts in concert with the MLH1 protein. Here we want to study how ASCIZ regulates the assembly of DNA repair centres, and if it does so with support by the BRCA1-BRCA2 proteins. We also want to know if DNA repair functions of the RAD51 protein are diminished when it is not located in repair centres, and we want to identify novel proteins involved in this process. Our preliminary data show that cells that lack ASCIZ become dramatically hypersensitive to DNA damaging agents that are similar to clinically used chemotherapy drugs. We hope that our studies may identify possible approaches to develop drugs against ASCIZ and related proteins in order to kill cancer cells more effectively.Read moreRead less
Function And Regulation Of ATM: Mechanistic Studies
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the mole ....The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the molecule will be important in its function in the cell. This project is designed to investigate the importance of other domains in the protein and also what it is that causes ATM to be activated. We have developed a methodology which allows us to introduce changes anywhere in the ATM gene and then test the effects of these changes in a biological read-cut assay. This approach will enable us to ascribe functional significance to any region of ATM. We will focus on regions where we have some preliminary evidence for activity. Finally we will carry out a mechanistic study to see how ATM is activated. These data will be useful in future design of molecules to interfere with the function of ATM in applications designed to make tumours more receptive to radiotherapy.Read moreRead less