Investigation Into The Roles Of Ena/VASP-Like And Protein Phosphatase 4C In DNA Damage Repair Via Homologous Recombination
Funder
National Health and Medical Research Council
Funding Amount
$57,139.00
Summary
The repair of DNA damage is a critical cellular mechanism that exists to ensure genomic stability. This project aims to investigate the role of the proteins Ena/VASP-Like and Protein Phosphatase 4C in DNA damage repair via homologous recombination. The DNA damage response pathway is an important area in the study of cancer and ageing, and the potential role of PP4C and EVL in homologous recombination needs to be investigated further.
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
Multi-domain Regulation Of DNA Damage Response Kinases
Funder
National Health and Medical Research Council
Funding Amount
$313,427.00
Summary
DNA damage plays a key role in the onset of cancer and the response to cancer therapies. Mutations in the Chk2 DNA damage response kinase are associated with increased cancer risk. We will study detailed mechanisms how phosphorylation of Chk2-like kinases contributes to normal copying of our DNA every time a cell divides, and how it regulates how Chk2 is activated. The studies will improve our understanding how cancer may originate and how cancer cells respond to chemo- or radiation therapy.
An In-vivo Model Of Acquired Chemoresistance In Small Cell Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$363,827.00
Summary
Lung cancer is a common and lethal disease in our community. In this project, we explore how a very aggressive form of lung cancer becomes resistant to chemotherapy. To do this, we use a new mouse model of lung cancer in which we can study how human lung cancer cells develop resistance to chemotherapy in vivo. Understanding these pathways will help us to better treat lung cancer with chemotherapy.
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
NK Cells As The Missing Link Between Anti-cancer Chemotherapy And CD8 T Cell Responses
Funder
National Health and Medical Research Council
Funding Amount
$488,478.00
Summary
Cytotoxic chemotherapy is the standard of care for most tumors but it rarely cures. The immune system has the capacity to destroy malignant cells but tumors usually evade immune destruction. Combination of chemo- immunotherapy may change this. DNA damage in tumor cells, caused by chemotherapy, induces expression of a set of molecules that activate Natural Killer cells. These cells can then activate anti-tumor T cells. Therapies that enhance this pathway may induce sustained anti-tumor effects.
I am a molecular and cellular biologist with particular interest in understanding the regulation of DNA damage surveillance pathway and its role in the maintenance of genome stability.
As women age, the quality of their eggs decline and their chance of having a healthy baby plummets. The accumulation of DNA damage within the egg, and the reduced ability to repair this damage, may be one cause of compromised reproductive success in older women. This project will investigate the ability of eggs to repair DNA damage during maternal aging and will explore the importance of DNA repair to fertility and the transmission of high quality genetic material to their offspring.