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.
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.
Telomere Structural Abnormalities In Cells Using Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$522,122.00
Summary
The continuing growth of cancers depends on their cells being able to prevent shortening of chromosome ends (telomeres). Some cancers, including very aggressive brain and connective tissue tumours, achieve this via the Alternative Lengthening of Telomeres (ALT) process. We have evidence that the telomere structure of normal cells prevents ALT. Here we will examine how the telomere structure of ALT-positive cancer cells is changed, and whether reversing these changes inhibits ALT.
Targeting Cancer-initiating Cells With DNA Methyltransferase Inhibitors: Single-cell Analysis To Decipher Molecular Mechanisms And Improve Efficacy.
Funder
National Health and Medical Research Council
Funding Amount
$175,000.00
Summary
Certain cancer cells, termed cancer-initiating cells (CICs), have special properties allowing them to drive cancer growth and disease progression. These cells are particularly sensitive to low-dose treatment with drugs called DNA methyltransferase inhibitors. Using cutting-edge "single-cell" technologies this project will determine how these drugs target CICs and identify new ways to increase treatment efficacy. This work will identify new clinical opportunities for prevention of cancer relapse.
Interaction Of TRF2 With DNA Repair Proteins In Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$297,246.00
Summary
10-15% of human cancers, including some of the most difficult-to-treat and aggressive, depend for their continuing growth on a molecular process called Alternative Lengthening of Telomeres (ALT). We have identified for the first time a protein whose normal role includes repressing ALT. We will study how this protein works, what its molecular partners are, and how these molecules interact with each other. This information is expected to lay the foundations for cancer treatments that target ALT.
Role Of MACROD2 Loss In DNA Repair, Chromosomal Instability And Development Of Colorectal Cancer: Clinical And Therapeutic Implications
Funder
National Health and Medical Research Council
Funding Amount
$772,871.00
Summary
The MACROD2 gene is deleted in one-third of human bowel cancers. We have discovered that MACROD2 deletion causes defective DNA repair and tumour chromosomal instability. Here, we will use novel laboratory models to show that MACROD2 loss actively promotes bowel cancer development. We will test the clinical implication of MACROD2 loss for predicting tumour therapy response and will investigate the potential of exploiting this deficiency for drug targeting.
Transcriptional And Epigenetic Regulation Of Epithelial Mesenchymal Plasticity In Breast Cancer Dissemination
Funder
National Health and Medical Research Council
Funding Amount
$670,964.00
Summary
Fuelling the spread of breast cancer are small clusters or individual cancer cells that escape into the blood (CTC) and bone marrow (DTC). Comprehensive analysis of these is prohibited by difficulty in purifying them, and their small numbers. Using two novel, validated mouse models for these cells, we have devised an approach that will identify new diagnostic and therapeutic targets in these compartments. These will ultimately provide avenues to improve breast cancer survival.
Identifying The Mechanism Of The G2 Phase UV Checkpoint And Repair Response Commonly Defective In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$569,656.00
Summary
The UV component of sunlight is the major environmental factor driving the development of melanoma. UV radiation can directly mutate genes resulting in their inability to perform normal functions which may contribute to cancer. Despite the high number of mutations directly attributable to UV radiation, the mechanisms known to repair these mutations are generally normal in melanoma. This research will investigate a repair mechanism we have identified that is commonly defective in melanomas.
Synthetic Lethality Screen Targeting A Defective Checkpoint In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$552,121.00
Summary
All cancers have defects in the mechanisms that regulate normal cell growth and division. These defects provide a growth advantage for the cancer, but can also be an Achilles Heel. In this project we will investigate targeting a defective control mechanism we found in a high proportion of melanomas. We will identify genes that when inhibited combine with the defective control to specifically kill tumour cells with this defect. Normal tissue is protected by its intact regulatory mechanism.