Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci

Quanz, Maria; Herbette, Aurélie; Sayarath, Mano; Koning, Leanne de; Dubois, Thierry; Sun, Jian‐Sheng; Dutreix, Marie

doi:10.1074/jbc.m111.320887

Cited by 80 publications

(112 citation statements)

References 67 publications

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“…While our studies were in progress, an independent study reported HSP90α-T5/7 phosphorylation by DNA-PK in response to DNA damage (42). These findings, together with ours described herein, highlight the ubiquitous nature of HSP90α phosphorylation by DNA-PK in response to DNA breaks.…”

Section: Discussionsupporting

confidence: 52%

“…1) (43). Second, apoptotic P-HSP90α-T5/7 is distributed broadly and rapidly in the apoptotic ring, contrary to the much weaker, focally distributed and delayed phosphorylation of HSP90α in γ-H2AX DDR foci (42). Third, the apoptotic ring, unlike DDR foci, is defective for DNA repair because it lacks many DDR effector proteins (such as 53BP1).…”

Section: Discussionmentioning

confidence: 94%

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Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

Solier

Kohn²,

Scroggins³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 94%

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

Solier

Kohn²,

Scroggins³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…A potent Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), has been found to inhibit radiation-induced double-strand break repair in tumor cells by reducing the phosphorylation of DNA-PKcs (29). Also in tumor cells, Hsp90 phosphorylation has been found to be correlated with DNA damage (30), and Rad51 focus formation at the damaged sites has been found to be delayed by NVP-AUY922, an inhibitor of Hsp90 (31). Another study has demonstrated that 17-allylamino-17-demethoxygeldanamycin (17-AAG) inhibits DSB repair in tumor cells by BRCA2 degradation; however, it has no effect in normal cells (32).…”

mentioning

confidence: 99%

Both the Charged Linker Region and ATPase Domain of Hsp90 Are Essential for Rad51-Dependent DNA Repair

et al. 2015

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“…For example, DNA-PKcs can be found in the centrosomes, and it regulates microtubule spindles during DNA damage and normal mitosis (16)(17)(18). In addition, DNA-PKcs locates in the cytoplasm and plasma membrane and performs other functions (19)(20)(21)(22)(23). One of the functions of the cytoplasmic DNAPKcs may be to phosphorylate protein kinase B (also known as Akt) at Ser-473 (20).…”

mentioning

confidence: 99%

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

Ho¹,

Mahanic

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Several ring between ring fingers (RBR) -domain proteins, such as Parkin and Parc, have been shown to be E3 ligases involved in important biological processes. Here, we identify a poorly characterized RBR protein, Ring Finger protein 144A (RNF144A), as the first, to our knowledge, mammalian E3 ubiquitin ligase for DNAPKcs. We show that DNA damage induces RNF144A expression in a p53-dependent manner. RNF144A is mainly localized in the cytoplasmic vesicles and plasma membrane and interacts with cytoplasmic DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). DNA-PKcs plays a critical role in the nonhomologous end-joining DNA repair pathway and provides prosurvival signaling during DNA damage. We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation. Depletion of RNF144A leads to an increased level of DNA-PKcs and resistance to DNA damaging agents, which is reversed by a DNA-PK inhibitor. Taken together, our data suggest that RNF144A may be involved in p53-mediated apoptosis through down-regulation of DNA-PKcs when cells suffer from persistent or severe DNA damage insults.endosome | DDR | transmembrane domain R ing Finger protein 144A (RNF144A) and RNF144B belong to the RNF144 family and are very conserved in higher eukaryotes. Both proteins contain an RING1-in between rings (IBR) -RING2 [termed the ring between ring fingers (RBR)] domain in the N terminus and a potential single-transmembrane (TM) domain in the C terminus. RBR domain-containing proteins usually possess an E3 ubiquitin ligase activity and are involved in regulation of the cell cycle and apoptosis (1-3). These proteins function like RING (Really Interesting New Gene)/HECT (Homologous to the E6AP Carboxyl Terminus) hybrids (i.e., they use their RING1 to bind E2s) but then transfer ubiquitin onto a conserved cysteine residue in the RING2 domain through a thioester linkage similar to the E3 thioester-linked ubiquitin intermediates in HECT-type E3 ligases (4). It has been shown that DNA damage induces RNF144B expression to promote cell apoptosis through regulation of the stability of p21 (5), BAX (1), and p73 (6). RNF144B shares 71% homology of amino acids with RNF144A.

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Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci

Cited by 80 publications

References 67 publications

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

Heat shock protein 90α (HSP90α), a substrate and chaperone of DNA-PK necessary for the apoptotic response

Both the Charged Linker Region and ATPase Domain of Hsp90 Are Essential for Rad51-Dependent DNA Repair

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

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