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.
The Role Of Nuclear Architecture In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$561,966.00
Summary
The goal of the proposed research is to understand how dynamic changes to the chromatin genome packaging network, interact with the DNA damage response and gene expression machinery, to repair damaged DNA and the impact this has on cancer biology. To do so we are combining cutting edge molecular biology techniques with innovative novel microscopy methods developed by our research team, that far exceed the spatiotemporal resolution currently used to study chromatin biology.
Understanding The Role Of SSB1 In Embryonic Development And Genome Maintenance
Funder
National Health and Medical Research Council
Funding Amount
$620,716.00
Summary
Normally DNA exists as a double helix where two strands are zipped together. When single-stranded (ss) DNA is exposed during various cellular processes it can be easily damaged and degraded by cellular enzymes, but is protected by ssDNA binding proteins (SSBs). We have identified two new SSBs (SSB1 and SSB2) that play a crucial role in DNA repair and will investigate the role and physiological function of these important proteins.
How Replication Stress Activates The Mitotic Telomere DNA Damage Response To Kill Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$486,467.00
Summary
We discovered a novel mechanism linking stress during DNA replication to difficulties with the cell division process, and identified how this turns on DNA damage response signals from the chromosome ends (i.e. “telomeres”). We have further identified that we can exploit this mechanism to kill cancer cells. In this project we will explore this newly discovered mechanism and identify how it can be targeted for therapeutic purposes.
Defective Repair Of Neuronal Activity-induced DNA Double Strand Breaks: A Novel Pathogenic Mechanism For Neurodegeneration In Ataxia-telangiectasia
Funder
National Health and Medical Research Council
Funding Amount
$570,821.00
Summary
The reason for degeneration of the hindbrain in patients with Ataxia-telangiectasia is unknown. Firing of neurons leads to breaks in the DNA that are normally repaired by ATM, the gene defective in Ataxia-telangiectasia, and failure to reset the system likely leads to abnormal gene expression and cell death. Here we use neuronal cell types derived from patient stem cells to elucidate how this novel disease mechanism may cause hindbrain degeneration and to test drugs that can overcome this.
Regulation And Function Of The Zinc-finger Protein ASCIZ In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$640,101.00
Summary
Each human cell is exposed to more than 10,000 spontaneous DNA damage events per day. Inaccurate repair of this is damage is believed to be one of the key events in the onset of cancer. We have discovered a protein called ASCIZ that contributes to the repair of DNA base damage, and also has a separate function in the onset of lung development. Here we want to study in detail the mechanism of how it functions in DNA repair and thereby keeps mutation rates low and prevents the onset of cancer.
Deciphering The Overlapping Roles Of SSB1 And SSB2 In The Regulation Of Haematopoiesis And Intestinal Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$996,631.00
Summary
Our work centres on elucidating the role of two newly identified and related single-stranded DNA binding protein (Ssb1 and Ssb2) in development of blood and gut system. When both genes are deleted mice die with 8 days of knockdown due to bone marrow failure and intestinal atrophy. Our double knockout model parallels the consequences of radiation damage on blood and gut system. Toxicity to these systems is a significant hindrance in delivering anti-tumor therapy.
TARGETING A NOVEL DNA-DAMAGE SIGNALING PATHWAY TO TREAT GLIOMAS
Funder
National Health and Medical Research Council
Funding Amount
$97,783.00
Summary
Glioblastoma Multiforme (GBM) is a high grade brain tumour for which current treatment modalities are inadequate. Tumour recurrence is almost inevitable and average life expectancy is measured in months. We have identified two proteins as potential therapeutic targets and demonstrated that depleting these proteins in vitro severely impacts on tumour cell viability. We will investigate the impact of targeting these proteins in mouse models of human gliomas and dissect the mechanism that leads to ....Glioblastoma Multiforme (GBM) is a high grade brain tumour for which current treatment modalities are inadequate. Tumour recurrence is almost inevitable and average life expectancy is measured in months. We have identified two proteins as potential therapeutic targets and demonstrated that depleting these proteins in vitro severely impacts on tumour cell viability. We will investigate the impact of targeting these proteins in mouse models of human gliomas and dissect the mechanism that leads to their upregulation in tumour cells.Read moreRead less
Is CYP11A1 Critical For The Vitamin D Photoprotective System In Skin?
Funder
National Health and Medical Research Council
Funding Amount
$517,567.00
Summary
Sunlight produces DNA damage. When inadequately repaired, this damage produces skin cancer. The vitamin D system in skin helps protect against this skin damage, but the vitamin D compounds involved and how they work is unclear. Recent data shows new vitamin D compounds with photoprotective activity and that vitamin D compounds increased expression of DNA repair proteins. These studies may enable pharmacological enhancement of protection from sunlight.
Identifying Regulators Of The DNA Damage Response And Tumourigenesis Using C. Elegans
Funder
National Health and Medical Research Council
Funding Amount
$514,367.00
Summary
By the age of 85, one in two men and one in three women in Australia will develop cancer. Regrettably, not all cancers respond to current therapies. Recently a new mechanism that prevents certain cancers from responding to chemotherapy has been identified, involving a protein called HIPK. We are using a simple model system, the nematode Caenorhabditis elegans, to discover ways in which this block to successful cancer treatment can be overcome, with the view to developing new therapeutic agents.