Investigation Of The Role Of The ATM Protein In Peroxisome Function And Biogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$250,756.00
Summary
Ataxia-telangiectasia (A-T) is a complex multisystem disease characterized by extreme sensitivity to ionizing radiation (X-rays) and susceptibility to cancer, however the most debilitating symptoms are neurodegeneration and susceptibility to bronchial infections. The gene (atm) which is mutated in this disease has recently been cloned and current research is focussed on the function of the protein (termed ATM) that this gene encodes. We have localized the ATM protein to the nucleus, where it pla ....Ataxia-telangiectasia (A-T) is a complex multisystem disease characterized by extreme sensitivity to ionizing radiation (X-rays) and susceptibility to cancer, however the most debilitating symptoms are neurodegeneration and susceptibility to bronchial infections. The gene (atm) which is mutated in this disease has recently been cloned and current research is focussed on the function of the protein (termed ATM) that this gene encodes. We have localized the ATM protein to the nucleus, where it plays a role in monitoring DNA damage, and also to vesicles in the cytoplasm of the cell. We have demonstrated that some of these vesicles are peroxisomes, vital cellular organelles involved in a wide range of metabolic functions. The importance of peroxisomes is evidenced by the severe abnormalities in patients with disorders of peroxisome formation and function. Interestingly many of the neurological features of these patients overlap with those displayed by A-T patients. We propose that abnormalities in peroxisomal function in A-T may contribute to the development of neurological symptoms and we plan to examine the function of peroxisomes in cells from A-T patients, and in tissues from A-T mutant mice. This work may help design new treatments to ameliorate the most debilitating aspects of this disease.Read moreRead less
Genome Maintenance And HSSB1, A Novel Player In The DNA Damage Response Pathway
Funder
National Health and Medical Research Council
Funding Amount
$646,822.00
Summary
We propose to characterize a novel player in the DNA damage response pathway. This study is expected to pave the way for the possible treatment of diseases that are caused by a nonfunctioning damage response pathway. There is an international effort to identify new proteins involved in this pathway and the funding of this proposal will provide leadership in Australia.
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
ATM Activation And Its Functional Importance In DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$555,541.00
Summary
ATM is the protein deficient in the human genetic disorder ataxia-telangiectasia (A-T). This syndrome is characterised by neurodegeneration and increased risk of cancer. ATM recognises damage in DNA and facilitates its repair to minimize the risk of genetic defects. The project is designed to investigate the mechanism of activation of ATM. This information is important to understand the role of ATM in preventing cancer.