DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139
Open accessAbstract
When mammalian cell cultures or mice are exposed to ionizing radiation in survivable or lethal amounts, novel mass components are found in the histone H2A region of two-dimensional gels. Collectively referred to as gamma, these components are formed in vivo by several procedures that introduce double-stranded breaks into DNA. gamma-Components, which appeared to be the only major novel components detected by mass or 32PO4 incorporation on acetic acid-urea-Triton X-100-acetic acid-urea-cetyltrimethylammonium bromide or SDS-acetic acid-urea-cetyltrimethylammonium bromide gels after exposure of cells to ionizing radiation, are shown to be histone H2AX species that have been phosphorylated specifically at serine 139. gamma-H2AX appears rapidly after exposure of cell cultures to ionizing radiation; half-maximal amounts are reached by 1 min and maximal amounts by 10 min. At the maximum, approximately 1% of the H2AX becomes gamma-phosphorylated per gray of ionizing radiation, a finding that indicates that 35 DNA double-stranded breaks, the number introduced by each gray into the 6 x 10(9) base pairs of a mammalian G1 genome, leads to the gamma-phosphorylation of H2AX distributed over 1% of the chromatin. Thus, about 0.03% of the chromatin appears to be involved per DNA double-stranded break. This value, which corresponds to about 2 x 10(6) base pairs of DNA per double-stranded break, indicates that large amounts of chromatin are involved with each DNA double-stranded break. Thus, gamma-H2AX formation is a rapid and sensitive cellular response to the presence of DNA double-stranded breaks, a response that may provide insight into higher order chromatin structures.
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H2AX is phosphorylated at serine 139 (γH2AX) in the vicinity of ssDNA, single-strand breaks, and double-strand breaks.
“The variant histone H2AX is phosphorylated at serine 139 (forming ␥H2AX) in the vicinity of single-stranded DNA (ssDNA), DNA single-or double-strand breaks (SSBs and DSBs, respectively) [38][39][40].”
From Gap-filling and bypass at the replication fork are both active mechanisms for tolerance of low-dose ultraviolet-induced DNA damage in the human genome (2014) · cites this paper as [38]
PhosphoS139 H2AX is a well-established marker for double-stranded DNA breaks.
“phosphoS139 H2AX, a well-established marker for double-stranded DNA breaks”
From Aggrecan, link protein and tenascin-R are essential components of the perineuronal net to protect neurons against iron-induced oxidative stress (2014) · cites this paper as [58]
Aged HSCs and muscle stem cells show increased numbers of nuclear foci staining for phosphorylated H2A.X, a marker of DNA double-strand breaks.
“aged HSCs and muscle stem cells (also called satellite cells) show an increased number of nuclear foci that stain for the phosphorylated form of the variant histone H2A.X (γH2A.X)36–38, which serves as a marker of DNA double-strand breaks39.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [39]
Experimental results have indicated that γ-H2AX foci colocalize with DSB repair factors (such as Rad51, BRCA1, Mre11, Rad50, and Nbs1) and participate in the repair of DSBs.
“Experimental results have indicated that γ-H2AX foci colocalize with DSB repair factors (such as Rad51, BRCA1, Mre11, Rad50, and Nbs1) [86, 91] and participate the repair of DSBs [85, 89, 90].”
From Markers of cellular senescence. Telomere shortening as a marker of cellular senescence (2016) · cites this paper as [90]
γ-H2AX foci reflect not only age-dependent irreversible DSBs (including telomere shortening) but also temporal accumulation of DSBs, which may be a result of massive ionizing radiation.
“Thus, γ-H2AX foci reflect – not only age-dependent irreversible DSBs (including telomere shortening) – but also temporal accumulation of DSBs, which may be a result of massive ionizing radiation (1 Gy of ionizing radiation, about 2 × 106 bp of DDBs, triggers phosphorylation of about 1% of the H2AX) [90].”
From Markers of cellular senescence. Telomere shortening as a marker of cellular senescence (2016) · cites this paper as [90]
Histone H2AX is phosphorylated at serine 139 by ATM to form γ-H2AX, which prevents double-strand breaks from being processed into chromosomal translocations.
“As an ATM substrate, histone H2AX is phosphorylated at Serine 139, which is referred to γ-H2AX and prevents DSBs from processing into chromosomal translocations [58, 59].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [58]
Phosphorylation of H2AX and S/T-Q sites occurs rapidly after DNA breaks.
“Phosphorylation of H2AX and S/T-Q sites, both of which are targets of ATM, occurs rapidly after DNA breaks.9,37,38”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [37]
Postmortem human AD samples show a significant increase in phosphorylated H2AX (γ-H2AX), a marker of cell senescence indicating double-stranded DNA breaks.
“WB analyses on postmortem human samples correlate those results with a significant increase in a phosphorylated form of the histone variant H2AX (γ-H2AX), a commonly used marker of cell senescence that indicates double-stranded DNA breaks [94] (Additional file 1: Fig. S8).”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [94]
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- Authors
- Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S., & Bonner, W. M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Bonner, William M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-03
- Volume
- 273
- Issue
- 10
- Pages
- 5858-5868
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1985775217
- Cited by
- 5,438
- References
- 41
- Citations by year
- 2026: 150 · 2025: 169 · 2024: 202 · 2023: 214 · 2022: 202 · 2021: 256 · 2020: 283 · 2019: 240 · 2018: 249 · 2017: 257 · 2016: 272 · 2015: 295 · 2014: 261 · 2013: 278 · 2012: 292
- FWCI
- 5.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA double-strand breaks, histone H2AX, γH2AX, ionizing radiation, chromatin structure, DNA damage response, phosphorylation kinetics
- MeSH terms
- Amino Acid Sequence, Animals, Cells, Cultured, Chromatin, DNA, Gamma Rays, Histones, Mice, Inbred Strains, Molecular Sequence Data, Nuclear Proteins, Peptide Fragments, Phosphorylation, Phosphoserine, Protein Kinases, Recombinant Proteins, Whole-Body Irradiation, Electrophoresis, Gel, Two-Dimensional, Mice
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