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bioRxiv · 10.1101/2020.08.04.237131

What p53 sees: ATM and ATR activation through crosstalk between DNA damage response pathways

Fedak, E. A.·Adler, F. R.·Abegglen, L. M.·Schiffman, J. D.
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Abstract

1Cells losing the ability to self-regulate in response to damage is a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because damage detection pathways vary in the rate and intensity with which they promote pro-apoptotic factors, the cells real challenge is to reconcile dissimilar signals. Crosstalk between repair pathways, crosstalk between pro-apoptotic signaling kinases, and signals induced by damage byproducts complicate the process further. The cells response to{gamma} and UV radiation neatly illustrates this concept. While these forms of radiation produce lesions associated with two different pro-apoptotic signaling kinases, ATM and ATR, recent experiments show that ATM and ATR react to both forms of radiation. To simulate the pro-apoptotic signal induced by{gamma} and UV radiation, we construct a mathematical model that includes three modes of crosstalk between ATM and ATR signaling pathways: positive feedback between ATM/ATR and repair proteins, ATM and ATR mutual upregulation, and changes in lesion topology induced by replication stress or repair. We calibrate the model to agree with 21 experimental claims about ATM and ATR crosstalk. We alter the model by adding or removing specific processes, then examine the effects of each process on ATM/ATR crosstalk by recording which claims the altered model violates. Not only is this the first mathematical model of ATM/ATR crosstalk, its implications provide a strong argument for treating pro-apoptotic signaling as a holistic effort rather than attributing it to a single dominant kinase.

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Fedak, E. A., Adler, F. R., Abegglen, L. M., Schiffman, J. D.. 2020-08-05. What p53 sees: ATM and ATR activation through crosstalk between DNA damage response pathways. https://doi.org/10.1101/2020.08.04.237131

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