ATM/ATR-Mediated Proteotoxic Stress Response and Its Implications for ATM Dependent Neurodegeneration

Isaac Corcoles-Saez, Kangzhen Dong, Erik Waskiewicz, Michael Costanzo¹, Charles M Boone¹, and Rita S Cha

School of Medical Sciences, Bangor University, Bangor, LL57 2UW, United Kingdom.

¹ University of Toronto, 160 College Street, Toronto, Ontario, M5S 3E1, Canada.

ATM and ATR are evolutionarily conserved mediators of the DNA damage response (DDR). ATM inactivation in humans leads to ataxia telangiectasia (AT), whose symptoms include neurodegeneration, cancer, diabetes, and immune system defects. We are interested in uncovering new functions of ATM that may provide further insights into the molecular basis underpinning every AT symptom. To this end, we are utilizing S. cerevisiae, a powerful model organism, and Mec1, the budding yeast ATM/ATR. We find that Mec1 inactivation leads to widespread protein aggregation and cell death in response to proteotoxic stress. Blocking protein synthesis or activation of autophagy rescues the lethality via aggregate-resolution; in contrast, neither alleviates DNA damage sensitivity of mec1 mutants, indicating that Mec1 mediates resistance to genotoxic- and proteotoxic- stress via different mechanisms. The human ATM also plays a crucial role in promoting survival in response to proteotoxic stress (Lee et al., 2018). Thus, proteostasis is conserved function of the yeast and human ATM/ATR proteins. Remarkably, Mec1 inactivation leads to acute sensitivity to HTT, the Huntington disease protein, unveiling a link between ATM/ATR signalling and aggregation status of a protein causing neurodegeneration. Together, these findings suggest that deficits in the ATM dependent proteostasis and the ensuring neuronal cell death may contribute to cerebellum ataxia, a hallmark of AT.

Lee, J.H., Mand, M.R., Kao, C.H., Zhou, Y., Ryu, S.W., Richards, A.L., Coon, J.J., and Paull, T.T. (2018). ATM directs DNA damage responses and proteostasis via genetically separable pathways. Sci. Signal. 11.