Abstract
Ataxia-telangiectasia mutated (ATM) is a serine/threonine protein kinase with a master regulatory function in the DNA damage response. In this role, ATM commands a complex biochemical network that signals the presence of oxidative DNA damage, including the dangerous DNA double-strand break, and facilitates subsequent repair. Here, we review the current state of knowledge regarding ATM-dependent chromatin remodelling and epigenomic alterations that are required to maintain genomic integrity in the presence of DNA double-strand breaks and/or oxidative stress. We will focus particularly on the roles of ATM in adjusting nucleosome spacing at sites of unresolved DNA double-strand breaks within complex chromatin environments, and the impact of ATM on preserving the health of cells within the mammalian central nervous system.This article is part of the themed issue 'Chromatin modifiers and remodellers in DNA repair and signalling'.
Highlights
Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Departments of Biochemistry & Molecular Biology and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1
As Ataxia-telangiectasia mutated (ATM) was identified in the early 1990s as a protein kinase targeting p53, the network of proteins that ATM phosphorylates has expanded to hundreds, spanning a multitude of pathways beyond the DNA damage response (DDR)
ATM’s roles and targets within the DDR are among its most well characterized, among which gH2AX is widely used as an indirect readout of double-strand break (DSB) repair
Summary
Motifs on more than 700 protein substrates [4]. The multitude of ATM substrates has been reviewed in [3]. These findings indicate an expansion of the network by which ATM monitors cellular oxidative stress and phosphorylates a specific set of downstream targets independent of those in its DNA damage response (DDR) role to respond to oxidative stress [8] This activation is attenuated by treatment with the ROS-scavenger N-acetylcysteine or low-oxygen (hypoxic) conditions [32]. The BRG1 catalytic subunit of the SWI/SNF chromatin remodelling complex contributes to effective gH2AX formation and, upon DNA damage, ATM phosphorylates BRG1S721 which greatly enhances BRG1 affinity for H2AX-containing nucleosomes and acetylated histone 3 [46,50] This localizes BRG1 at DSB sites, where its chromatin remodelling activity contributes to enhanced gH2AX formation and spreading [46,50]. ATM phosphorylation of RNF20/40 is required for the subsequent action of ACF1-SNF2H p
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