Cell Death and Survival Pathways Involving ATM Protein Kinase

Toshihiko Aki,Koichi Uemura

doi:10.3390/genes12101581

Abstract

Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.

Highlights

Cellular genomic DNA is always exposed to the risk of damage caused by ultraviolet light (UV), ionizing irradiation (IR), and exposure to chemicals, what is collectively called genotoxic stress [1,2]
There are an ever-growing number of cell death modes, we pick up apoptosis, necroptosis, and ferroptosis; ataxia telangiectasia mutated kinase (ATM) is suggested to be involved in these modes of cell death
Recent research progress is revealing that necroptosis, parthanatos, and ferroptosis must be taken into accounts in the research field of ATM-dependent cell death

Summary

Introduction

Cellular genomic DNA is always exposed to the risk of damage caused by ultraviolet light (UV), ionizing irradiation (IR), and exposure to chemicals, what is collectively called genotoxic stress [1,2]. When a DSB is generated in cells, the MRN complex recognizes the ends of DNA breaks and recruits ATM to the ends, where ATM self-activates through autophosphorylation at ser-1981 [15,16]. Massive genotoxic stress surpassing the cellular ability to repair the resulting DNA damage should lead to cell death or the development of cancer. In this brief review, we intend to provide minimal essential information of fundamental mechanism of cell death for the researchers who are interested in ATM and cell death. There are an ever-growing number of cell death modes, we pick up apoptosis, necroptosis, and ferroptosis; ATM is suggested to be involved in these modes of cell death

Role of ATM in Apoptosis

Role of ATM in Necroptosis

Role of ATM in Ferroptosis

Role of ATM

Concluding Remarks and Future Perspectives