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Restoring metabolic balance in Ataxia-Telangiectasia
ATM, the gene mutated in Ataxia-Telangiectasia (A-T), is
serine/treonine kinase controlling different aspects of cell biology in response to DNA damage such as cell cycle progression, DNA repair and cell survival. The molecular and cellular events underlying the responses controlled by ATM are poorly understood. Recently, we have identified novel ATM targets involved in the control of anabolic and antioxidant cellular metabolism such as the Pentose Phosphate Pathway (PPP) and in the coordination of cell cycle progression such as Cep63. ATM mediated stimulation of the PPP might promote nucleotide and anti oxidant molecule synthesis required by cells to face DNA damaging insults. Stimulation of the PPP revealed the existence of a direct link between ATM and complex metabolic pathways involved in basic cellular functions essential for life. Consistent with our findings additional published evidence points at a role for ATM in the control of cellular processes not directly involved in DNA repair such as autophagy, glucose metabolism and mitochondrial function.
In the past few years we have established several assays based on
cell free systems and human cell cultures to elucidate the biochemical bases of ATM and its related kinase ATR in vertebrate organisms. We will now use these establish assays and we will develop new ones to understand the molecular and physiological bases of ATM dependent control of cellular metabolism.
These studies will be important to understand how ATM controls cell
survival and might be helpful to design novel therapeutic interventions restore cellular functions controlled by ATM that are altered or absent in A-T cells, bypassing the requirement for ATM.
ATM is a serine/threonine protein kinase that senses DNA damage and
activates a pathway that leads to the phosphorylation of proteins such as Brca1, Nbs1, Chk1, Chk2, p53 and many others .
ATM can be activated by double strand breaks in the DNA (DSBs) ,
which are among the most harmful form of DNA damage. DSBs can indeed lead to chromosome loss and rearrangements with consequent loss of genetic information.
We recently discovered a link between ATM and cellular metabolism,
which might be responsible for some of A-T phenotypes . We found that ATM regulates the pentose phosphate pathway (PPP), a major source of cellular constituents such as nucleotide precursors and antioxidant reducing agents such as NADPH. We showed that ATM activation up regulates the PPP by increasing the activity of the rate limiting enzyme glucose-6-phospate dehydrogenase (G6PD), which is important in preventing defects in cell growth and signaling, anomalous embryonic development, as well as
degenerative diseases. . This regulation requires ATM dependent phoshorylation of nuclear Heat shock protein 27 (Hsp27), which is exported to the cytoplasm where it is able to directly bind G6PD and stimulate its activity.
These findings provided insight on how ATM is linked to carbon
metabolism to facilitate DNA repair and prevent reactive oxygen species (ROS) toxicity. ATM has been shown to be directly activated by ROS , suggesting that damaged DNA is not the only stressful signal activating ATM. Overall, these observations indicate a possible role for ATM in redox sensing and control, which may be critical for cell survival even in the absence of apparent DNA damage. Elevated ROS levels may directly activate ATM protein kinase that can in turn up regulate the PPP, resulting in NADPH production. The NADPH could then reduce oxidised glutathione, which protects the cell from the harmful effects of ROS. This could explain increased neurodegeneration in non-proliferating cells with an ATM- / - background. Consistent with this we have shown that low antioxidants levels correlate with the severity of neurological impairment in A-T patients and that steroid treatment mediated improvement of clinical symptoms correlates with higher reducing agents production To understand the molecular and physiological events underlying the pathogenesis of A-T it will be important to clarify the molecular and physiological bases of ATM dependent control of cellular metabolisms. Characterization of metabolic imbalances in A-T cells will also facilitate the identification of natural substances and synthetic molecules that might be used to restore cellular functions impaired in A-T, bypassing the requirement for ATM kinase in their regulation. We expect that these studies will provide fundamental clues that will be useful to design therapeutic interventions aimed at modifying the natural course of this disease.
To identify novel strategies to restore metabolic balance in A-T cells
To gain further insights into ATM dependent regulation of cellular
metabolism we have recently performed a metabolic profile of early passage cells derived from A-T patients. From the initial evaluation of these dataset we found that antioxidant, pentose phosphate, nucleotide and lipid metabolism pathways were the most impaired in A-T cells.
To verify whether metabolic imbalances are directly involved in A-T cell
proliferation defects, diminished survival, accelerated senescence and low tolerance for DNA damage we will design experiments to restore normal levels of compounds found altered in A-T cells. To reach this goal and alleviate these defects we will use cell permeable natural compounds and drugs acting on alternative pathways, which should in theory be able to attenuate metabolic defects found in A-T cells. We will use the ability of these treatments to improve colony formation of non-transformed A-T cells as main readout for these experiments.
Experiments described in this project will be carried out over the course
of 4 years. The first year of this project will be dedicated to generate, acquire and test all the reagents necessary for the functional assays described here and to confirm the results of the preliminary metabolic analysis. We will then analyse the effects of A-T metabolic imbalances on cell proliferation in non-transformed cells as described. These tasks will be carried out one experienced postdoctoral scientist.
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CURRICULUM VITAE KENNETH ALEXANDER MURRAY Date of Birth: Place of Birth: London, Ontario Citizenship: Marital Status: Married (3 children) Undergraduate Education: Bishop Ridley CollegeSt. Catharines, OntarioUniversity of Western Ontario, London, OntarioGraduate Bachelor of Arts (BA) Degrees/Certificates: Graduated MD, Dalhousie University Halifax, Nova ScotiaFellow Ameri