Feature Article: Heat shock protein 90? (HSP90?), a substrate and chaperone of DNA-PK necessary for the apoptotic response.

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Feature Article: Heat shock protein 90? (HSP90?), a substrate and chaperone of DNA-PK necessary for the apoptotic response.

Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):12866-72

Authors: Solier S, Kohn KW, Scroggins B, Xu W, Trepel J, Neckers L, Pommier Y

Abstract
The "apoptotic ring" is characterized by the phosphorylation of histone H2AX at serine 139 (?-H2AX) by DNA-dependent protein kinase (DNA-PK). The ?-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 90? (HSP90?) in biochemical assays, we investigated whether HSP90? is involved in the apoptotic ring. Here we show that HSP90? is phosphorylated by DNA-PK on threonines 5 and 7 early during apoptosis and that both phosphorylated HSP90? and DNA-PK colocalize in the apoptotic ring. We also show that DNA-PK is a client of HSP90? and that HSP90? is required for full DNA-PK activation, ?-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 HSP90? is a substrate and chaperone of DNA-PK in the apoptotic response. The response of phosphorylated HSP90? to TRAIL and its localization to the ?-H2AX ring represent epigenetic features of apoptosis that offer insights for studying and monitoring nuclear apoptosis.

PMID: 22753480 [PubMed - in process]

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