"ATR activation in response to ionizing radiation: still ATM territory"

Myriam Cuadrado,Oscar Fernandez-Capetillo,Barbara Martinez-Pastor

doi:10.1186/1747-1028-1-7

Myriam Cuadrado, Oscar Fernandez-Capetillo + Show 1 more

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https://doi.org/10.1186/1747-1028-1-7

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Journal: Cell Division	Publication Date: May 17, 2006
Citations: 49	License type: cc-by

Affiliation: Spanish National Cancer Research Centre

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Unrepaired DNA double-strand breaks (DSBs) are a major cause for genomic instability. Therefore, upon detection of a DSB a rapid response must be assembled to coordinate the proper repair/signaling of the lesion or the elimination of cells with unsustainable amounts of DNA damage. Three members of the PIKK family of protein kinases -ATM, ATR and DNA-PKcs- take the lead and initiate the signaling cascade emanating from DSB sites. Whereas DNA-PKcs activity seems to be restricted to the phosphorylation of targets involved in DNA repair, ATM and ATR phosphorylate a broad spectrum of cell cycle regulators and DNA repair proteins. In the canonical model, ATM and ATR are activated by two different types of lesions and signal through two independent and alternate pathways. Specifically, ATR is activated by various forms of DNA damage, including DSBs, arising at stalled replication forks ("replication stress"), and ATM is responsible for the signaling of DSBs that are not associated with the replication machinery throughout the cell cycle. Recent evidence suggests that this model might be oversimplified and that coordinated crosstalk between ATM and ATR activation routes goes on at the core of the DNA damage response.

Highlights

Accumulation of DNA damage at the cellular level is linked to a number of phenotypes at the organism level including progeria, neurodegeneration and cancer
If DNA double-strand break (DSB) arise at the replication fork, activation of the ATM and Rad3-related (ATR) pathway is responsible for the signaling of damaged DNA
In addition to Ataxia Telangiectasia mutated (ATM) and ATR, which are rapidly recruited to the break sites and are the earliest transducers of the DNA damage response, the strength of each pathway is reinforced by the subsequent activation of an additional downstream kinase

Summary

Introduction

Accumulation of DNA damage at the cellular level is linked to a number of phenotypes at the organism level including progeria, neurodegeneration and cancer. If DSBs arise at the replication fork (the still not fully defined concept of "replication stress"), activation of the ATR pathway is responsible for the signaling of damaged DNA. And in agreement with its general role in cell-cycle checkpoints [2], ATM is responsible for the signaling of other types of DSBs that are not restricted to replicating cells. One possible interpretation is that this phosphorylation is derived from "accidental" phosphorylation of Chk by ATM, at the high doses of IR used in this type of experiment [3]. Both Chk and ATR are known regulators of the G2/M checkpoint in response to IR. Data coming from several groups resolves this controversy and provides a novel molecular framework to understand the cellular responses to IR [7,8,9,10]

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