Histone H2AX Is Phosphorylated in an ATR-dependent Manner in Response to Replicational Stress*

By Irene M. Ward, Junjie Chen. Journal of Biological Chemistry, 2001

1,229 citations recorded by the source corpus.

H2AX, a member of the histone H2A family, is rapidly phosphorylated in response to ionizing radiation. This phosphorylation, at an evolutionary conserved C-terminal phosphatidylinositol 3-OH-kinase-related kinase (PI3KK) motif, is thought to be critical for recognition and repair of DNA double strand breaks. Here we report that inhibition of DNA replication by hydroxyurea or ultraviolet irradiation also induces phosphorylation and foci formation of H2AX. These phospho-H2AX foci colocalize with proliferating cell nuclear antigen (PCNA), BRCA1, and 53BP1 at the arrested replication fork in S phase cells. This response is ATR-dependent but does not require ATM or Hus1. Our findings suggest that, in addition to its role in the recognition and repair of double strand breaks, H2AX also participates in the surveillance of DNA replication.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/a3b867e8e0682e4b4f28693f5148d82313faf7d3

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Citations in the corpus

DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. (2013, neutral): “phosphorylation of Chk2 and SMC1 [96,97].”
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).”
The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more? (2008, background): “X in response to UV and replication stress but not in response to IR [Ward and Chen, 2001; Ward et al., 2004].”
Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle (2003, background): “DSBs arising from replication fork blockage after UV irradiation result in -H2AX focus formation (31, 71), and PFGE measurements show that aphidicolin induces DSBs specifically during the S phase (50).”
DNA damage sensing by the ATM and ATR kinases. (2013, background): “On the other hand, ATR was shown to phosphorylate H2AX in response to DNA replication stress, which may recruit ATM to the chromatin adjacent to stressed replication forks (Ward and Chen 2001).”
Cellular response to hyperosmotic stresses. (2007, background): “Thus Mre11 exonuclease is a nuclear protein that normally binds rapidly to DNA breaks, beginning the process of repair (64), and histone H2AX becomes phosphorylated at DNA doublestranded breaks caused by a number of agents (90, 250, 309), both being prerequisite for successful DNA repair (45, 229).”