ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks*

By S. Burma, B. Chen, Michael M. Murphy, A. Kurimasa, David J. Chen. Journal of Biological Chemistry, 2001

2,043 citations recorded by the source corpus.

A very early step in the response of mammalian cells to DNA double-strand breaks is the phosphorylation of histone H2AX at serine 139 at the sites of DNA damage. Although the phosphatidylinositol 3-kinases, DNA-PK (DNA-dependent proteinkinase), ATM (ataxia telangiectasiamutated), and ATR (ATM andRad3-related), have all been implicated in H2AX phosphorylation, the specific kinase involved has not yet been identified. To definitively identify the specific kinase(s) that phosphorylates H2AX in vivo, we have utilized DNA-PKcs−/− and Atm−/− cell lines and mouse embryonic fibroblasts. We find that H2AX phosphorylation and nuclear focus formation are normal in DNA-PKcs−/− cells and severely compromised in Atm−/− cells. We also find that ATM can phosphorylate H2AX in vitro and that ectopic expression of ATM in Atm−/− fibroblasts restores H2AX phosphorylation in vivo. The minimal H2AX phosphorylation in Atm−/− fibroblasts can be abolished by low concentrations of wortmannin suggesting that DNA-PK, rather than ATR, is responsible for low levels of H2AX phosphorylation in the absence of ATM. Our results clearly establish ATM as the major kinase involved in the phosphorylation of H2AX and suggest that ATM is one of the earliest kinases to be activated in the cellular response to double-strand breaks.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8da31d7c306ecb7ee8079b7a7378009c6466a704

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Citations in the corpus

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more? (2008, background): “X [Burma et al., 2001; Stiff et al., 2004].”
DNA damage and its links to neurodegeneration (2014, neutral): “Chromatin modifications in the DDR The formation of DNA DSBs triggers various chromatin modifications, including polyADP-ribosylation mediated by PARP1; histone acetylation/deacetylation mediated by HAT such as p300, MOF and TIP60, and HDAC, such as HDAC1, SIRT1 and SIRT6; and ATMdependent H2AX phos”
How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers (2007, background): “The human H2A variant H2AX has been shown to be phosphorylated by the 'ataxia telangiectasia mutated' kinase (ATM) at S139 (known as γH2AX) upon induction of double-strand break”
Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks (2003, background): “ATM is a primary DNA damage sensor that phosphorylates numerous targets, including Nbs1 and H2AX, in response to DSB”
DNA damage-induced alterations in chromatin contribute to genomic integrity and age-related changes in gene expression (2008, positive): “We then investigated whether SIRT1 recruitment is dependent on histone H2AX, one of the immediate targets of ATM (Burma et al., 2001).”
ATM and related protein kinases: safeguarding genome integrity (2003, background): “H2AX phosphorylation — a very early event in the cascade induced by DSBs — was reported to be ATM dependent following DSB inductio”
Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “More generally, it appears that there is a conserved mechanism for apical DDR kinase recruitment to DNA damage sites that involves similar interaction motifs in the C termini of human Ku80-, NBS1-, and ATRIP-mediating interactions with DNA-PKcs, ATM, and ATR, respectively (Falck et al. 2005).”
Regulation and mechanisms of mammalian double-strand break repair (2003, background): “…event (1–3min) during foci formation is the phosphorylation of histone H2AX at S139 by ATM or other wortmannin-sensitive PIKKs (Paull et al., 2000; Burma et al., 2001), followed by colocalization of BRCA1, RAD54, and either RAD50 or RAD51 (Scully et al., 1997a; Nelms et al., 1998; Tan et al.,…”
ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation (2004, background): “An earlier study carried out on primary and transformed MEFs reported that H2AX phosphorylation is ATM dependent (23).”
Mechanisms of human DNA repair: an update. (2003, neutral): “It also phosphorylates 2AX (Burma et al., 2001).”
A splicing mutation affecting expression of ataxia–telangiectasia and Rad3–related protein (ATR) results in Seckel syndrome (2003, neutral): “Current data suggests that after exposure to ultraviolet radiation, ATR phosphorylates similar substrates to those phosphorylated by ATM after ionizing radiation, including p53, Rad17, Nbs1 and H2AX, a variant form of the histone H2A (refs”
Mechanism and regulation of class switch recombination. (2008, background): “Within seconds after formation of a DSB induced by ionizing radiation or by a restriction enzyme, the extended C-terminal tail of H2AX is phosphorylated by a PIKK kinase, most frequently ATM (166, 167), and this phosphorylation spreads over a region estimated to span up to a megabase surrounding the”