Formation of Dynamic γ-H2AX Domains along Broken DNA Strands Is Distinctly Regulated by ATM and MDC1 and Dependent upon H2AX Densities in Chromatin
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A hallmark of the cellular response to DNA double-strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate gamma-H2AX. Here, we demonstrate that gamma-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which gamma-H2AX forms does not spread as DSBs persist; rather, gamma-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate gamma-H2AX, only ATM promotes gamma-H2AX formation to maximal distance and maintains gamma-H2AX densities. MDC1 is essential for gamma-H2AX formation at high densities near DSBs, but not for generation of gamma-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance, of gamma-H2AX formed. Our data suggest that H2AX fuels a gamma-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX.
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ATR and ATM phosphorylate histone H2AX at Ser-139 (γH2AX) in response to DNA double-strand breaks, and γH2AX spreads along DNA up to 200-400 kb and helps recruit proteins involved in DNA damage repair and checkpoint activation.
“ATR and ATM also phosphorylate histone H2AX at Ser-139 (γH2AX) in response to DNA double-strand breaks (DSBs), which spreads along the DNA up to 200–400 kb and helps in the recruitment of proteins involved in DNA damage repair and checkpoint activation [29].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [29]
ATR and ATM allow H2AX phosphorylation and spreading at damage sites, which changes chromatin structure near the damage and executes DNA repair through the HR pathway.
“Additionally, it is well established that ATR and ATM allow H2AX phosphorylation and spreading at the damage site, which changes the chromatin structure near the damage site and executes DNA repair through the HR pathway [21-23, 26, 63].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [21]
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Retracted
- Authors
- Savic, V., Yin, B., Maas, N. L., Bredemeyer, A. L., Carpenter, A. C., Helmink, B. A., Yang-Iott, K. S., Sleckman, B. P., & Bassing, C. H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Washington University in St. Louis (US)
- Corresponding author
- Bassing, Craig H.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 34
- Issue
- 3
- Pages
- 298-310
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2744111
- OpenAlex
- W2036749550
- Cited by
- 204
- References
- 48
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 14 · 2023: 9 · 2022: 11 · 2021: 12 · 2020: 14 · 2019: 12 · 2018: 7 · 2017: 12 · 2016: 9 · 2015: 9 · 2014: 12 · 2013: 22 · 2012: 15
- FWCI
- 7.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1574 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion)
- Funders
- National Cancer Institute (R01CA125195)
- National Institute of Allergy and Infectious Diseases (R01AI074953, T32AI055428)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- γH2AX, DNA double-strand breaks, ATM, MDC1, DNA-PKcs, H2AX phosphorylation, DNA repair, G1 phase, chromatin
- MeSH terms
- Animals, B-Lymphocytes, Chromatin, DNA, DNA Damage, DNA-Binding Proteins, Endonucleases, Histones, Nuclear Proteins, Recombination, Genetic, Thymus Gland, Tumor Suppressor Protein p53, G1 Phase, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, Genes, T-Cell Receptor alpha, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Ataxia Telangiectasia Mutated Proteins
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