Mathematical Model of ATM Activation and Chromatin Relaxation by Ionizing Radiation.

Yongfeng Li,Francis A Cucinotta

doi:10.3390/ijms21041214

Yongfeng Li, Francis A Cucinotta

Open Access

https://doi.org/10.3390/ijms21041214

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Abstract

We propose a comprehensive mathematical model to study the dynamics of ionizing radiation induced Ataxia-telangiectasia mutated (ATM) activation that consists of ATM activation through dual mechanisms: the initiative activation pathway triggered by the DNA damage-induced local chromatin relaxation and the primary activation pathway consisting of a self-activation loop by interplay with chromatin relaxation. The model is expressed as a series of biochemical reactions, governed by a system of differential equations and analyzed by dynamical systems techniques. Radiation induced double strand breaks (DSBs) cause rapid local chromatin relaxation, which is independent of ATM but initiates ATM activation at damage sites. Key to the model description is how chromatin relaxation follows when active ATM phosphorylates KAP-1, which subsequently spreads throughout the chromatin and induces global chromatin relaxation. Additionally, the model describes how oxidative stress activation of ATM triggers a self-activation loop in which PP2A and ATF2 are released so that ATM can undergo autophosphorylation and acetylation for full activation in relaxed chromatin. In contrast, oxidative stress alone can partially activate ATM because phosphorylated ATM remains as a dimer. The model leads to predictions on ATM mediated responses to DSBs, oxidative stress, or both that can be tested by experiments.

Highlights

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a key role in the chromatin remodeling and activation of cell cycle checkpoint in response to the DNA double strand breaks (DSBs) induced by ionizing radiation (IR)
Upon activation ATM functions as an upstream signaling protein that phosphorylates a variety of substrates, such as H2AX, p53, Chk2, ATF2, and KAP-1, that are important for the DNA damage response and cell cycle control
Experimental studies have shown that ATM activation involves the in trans autophosphorylation and the acetylation by Tip60 and is induced by the MRN complex consisting of the proteins MRE11, RAD50 and NBM, oxidative stress, DSB, and so on

Summary

Introduction

Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase that plays a key role in the chromatin remodeling and activation of cell cycle checkpoint in response to the DNA double strand breaks (DSBs) induced by ionizing radiation (IR). Upon activation ATM functions as an upstream signaling protein that phosphorylates a variety of substrates, such as H2AX, p53, Chk, ATF2, and KAP-1, that are important for the DNA damage response and cell cycle control. Ataxia telangiectasia mutated (ATM) is a protein kinase of the PIKK superfamily, which mediates cellular response to DNA damage by regulating large number of substrates including ATF2, CHK2, KAP-1, MDM2, NBS1, p53, and so on. As an upstream signaling protein, ATM plays a crucial role in the DNA damage response, repair pathways, and cell cycle arrest; and how ATM is activated is important for the downstream signaling pathway in response to DNA damage

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