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Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response
- Source :
- Proceedings of the National Academy of Sciences. 109:12866-12872
- Publication Year :
- 2012
- Publisher :
- Proceedings of the National Academy of Sciences, 2012.
-
Abstract
- The “apoptotic ring” is characterized by the phosphorylation of histone H2AX at serine 139 (γ-H2AX) by DNA-dependent protein kinase (DNA-PK). The γ-H2AX apoptotic ring differs from the nuclear foci patterns observed in response to DNA-damaging agents. It contains phosphorylated DNA damage response proteins including activated Chk2, activated ATM, and activated DNA-PK itself but lacks MDC1 and 53BP1, which are required to initiate DNA repair. Because DNA-PK can phosphorylate heat shock protein 90α (HSP90α) in biochemical assays, we investigated whether HSP90α is involved in the apoptotic ring. Here we show that HSP90α is phosphorylated by DNA-PK on threonines 5 and 7 early during apoptosis and that both phosphorylated HSP90α and DNA-PK colocalize in the apoptotic ring. We also show that DNA-PK is a client of HSP90α and that HSP90α is required for full DNA-PK activation, γ-H2AX formation, DNA fragmentation, and apoptotic body formation. In contrast, HSP90 inhibition by geldanamycin markedly enhances TRAIL-induced DNA-PK and H2AX activation. Together, our results reveal that HSP90α is a substrate and chaperone of DNA-PK in the apoptotic response. The response of phosphorylated HSP90α to TRAIL and its localization to the γ-H2AX ring represent epigenetic features of apoptosis that offer insights for studying and monitoring nuclear apoptosis.
- Subjects :
- DNA repair
DNA damage
Blotting, Western
Apoptosis
DNA Fragmentation
DNA-Activated Protein Kinase
environment and public health
Histones
TNF-Related Apoptosis-Inducing Ligand
chemistry.chemical_compound
Cell Line, Tumor
Commentaries
Heat shock protein
In Situ Nick-End Labeling
Humans
Fluorometry
HSP90 Heat-Shock Proteins
Phosphorylation
RNA, Small Interfering
Multidisciplinary
biology
Geldanamycin
Flow Cytometry
Apoptotic body
Hsp90
MDC1
Cell biology
Enzyme Activation
enzymes and coenzymes (carbohydrates)
Microscopy, Fluorescence
chemistry
biology.protein
DNA fragmentation
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....3e2d9d0240b2c77f472d0f893151711a