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Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability
- Source :
- The EMBO journal. 26(5)
- Publication Year :
- 2006
-
Abstract
- Fanconi anemia (FA) is a chromosome fragility syndrome characterized by bone marrow failure and cancer susceptibility. The central FA protein FANCD2 is known to relocate to chromatin upon DNA damage in a poorly understood process. Here, we have induced subnuclear accumulation of DNA damage to prove that histone H2AX is a novel component of the FA/BRCA pathway in response to stalled replication forks. Analyses of cells from H2AX knockout mice or expressing a nonphosphorylable H2AX (H2AX(S136A/S139A)) indicate that phosphorylated H2AX (gammaH2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to gammaH2AX is BRCA1-dependent and cells deficient or depleted of H2AX show an FA-like phenotype, including an excess of chromatid-type chromosomal aberrations and hypersensitivity to MMC. This MMC hypersensitivity of H2AX-deficient cells is not further increased by depleting FANCD2, indicating that H2AX and FANCD2 function in the same pathway in response to DNA damage-induced replication blockage. Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent chromosome instability.
- Subjects :
- DNA Replication
congenital, hereditary, and neonatal diseases and abnormalities
DNA damage
Cell Survival
Ultraviolet Rays
Mitomycin
environment and public health
General Biochemistry, Genetics and Molecular Biology
Article
Cell Line
Histones
Mice
Fanconi anemia
Chromosome instability
hemic and lymphatic diseases
Cell Line, Tumor
Chromosomal Instability
FANCD2
medicine
Animals
Humans
Immunoprecipitation
Molecular Biology
Nucleic Acid Synthesis Inhibitors
Mice, Knockout
General Immunology and Microbiology
biology
BRCA1 Protein
General Neuroscience
Fanconi Anemia Complementation Group D2 Protein
Cell Cycle
Histone H2AX
DNA replication
medicine.disease
Flow Cytometry
Immunohistochemistry
Fanconi Anemia Complementation Group Proteins
Chromatin
enzymes and coenzymes (carbohydrates)
Histone
biology.protein
Cancer research
biological phenomena, cell phenomena, and immunity
DNA Damage
HeLa Cells
Signal Transduction
Subjects
Details
- ISSN :
- 02614189
- Volume :
- 26
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The EMBO journal
- Accession number :
- edsair.doi.dedup.....8d0335e944a87aa967af26fcecfe8eb4