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 Function Of Recql4 In DNA Replication And Genome Maintenance
Funder
National Health and Medical Research Council
Funding Amount
$698,447.00
Summary
We are interested in understanding how cancer forms. We are using information from human cancers to understand how a protein causes cancer. We are using models to understand how mutations in this protein give rise to bone cancer. These models are used together with detailed biochemistry to understand how the mutations affect protein function.
A Tumour Suppressor Pathway That Removes DNA-RNA Hybrids
Funder
National Health and Medical Research Council
Funding Amount
$935,780.00
Summary
DNA:RNA hybrids are found normally in our chromosomes. But, the regions where DNA:RNA hybrids form are linked to chromosome changes that occur during breast and blood cancer development. We have uncovered why these chromosome changes occur, and have linked it to the important function of a cancer-associated gene called FANCM. Our study is exploring this important finding that has implications for both the cause and treatment of cancer.
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.
The Structure And Organization Of The Mitochondrial Genome In Health And Mitochondrial Disease
Funder
National Health and Medical Research Council
Funding Amount
$553,646.00
Summary
Mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction have been associated with a wide range of multi-system human diseases, although much remains to be learnt about molecular mechanisms in the pathogenesis of these diseases. Our goal is to understand how the expression of the mitochondrial DNA is regulated by mtDNA-binding proteins that will allow us to provide important insights into the molecular mechanisms of mitochondrial diseases.
The Mutagenic Influence Of 5-methylcytosine And Its Relevance For Cancer Treatment
Funder
National Health and Medical Research Council
Funding Amount
$844,462.00
Summary
Over time our cells accumulate damage to their DNA, which introduces mistakes in the genetic code. These mistakes can alter genes that regulate cell growth and survival and, in this way, they begin the process of turning a normal cell into a cancer. This research is investigating the cellular repair mechanisms that safeguard against DNA damage. Manipulating these repair mechanisms may offer a new way to treat cancer, by selectively inducing DNA damage within cancer cells.
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.