The apoptotic ring: A novel entity with phosphorylated histones H2AX and H2B, and activated DNA damage response kinases

Solier, Stéphanie; Pommier, ﻿Yves

doi:10.4161/cc.8.12.8865

Cited by 110 publications

(110 citation statements)

References 30 publications

(50 reference statements)

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“…In the rest of the study, we focused on TRAIL-induced apoptosis because TRAIL induces a robust HSP90α-T5/7 phosphorylation and initiates its effect from the cell surface without targeting chromatin, thus eliminating the possibility that DNA-PK activation could be initiated by agents that directly induce DNA damage. Also, TRAIL has been the focus of our recent studies on chromatin modifications in the early stages of apoptosis under conditions similar to those presented here (24)(25)(26).…”

Section: Hsp90α Phosphorylation Is An Extensive and Early Process Duringmentioning

confidence: 87%

“…Because we previously showed that the apoptotic DDR (including phosphorylation of H2AX, DNA-PK, Chk2, and ATM) is initiated within 1 h after TRAIL treatment (24)(25)(26), we compared the kinetics of HSP90α and H2AX phosphorylation in response to TRAIL. Fig.…”

Section: Hsp90α Phosphorylation Is An Extensive and Early Process Duringmentioning

confidence: 99%

“…One of the early landmarks of apoptosis is the phosphorylation of histone H2AX at serine 139 (γ-H2AX) by activated DNAdependent protein kinase (DNA-PK) (24)(25)(26)(27). We previously reported that this epigenetic process begins at the periphery of the nucleus and forms a characteristic "apoptotic ring" in confocal microscopy imaging before diffusing to the whole chromatin and persisting at later stages of apoptosis even when the nucleus fragments into apoptotic bodies.…”

mentioning

confidence: 99%

“…We previously reported that this epigenetic process begins at the periphery of the nucleus and forms a characteristic "apoptotic ring" in confocal microscopy imaging before diffusing to the whole chromatin and persisting at later stages of apoptosis even when the nucleus fragments into apoptotic bodies. The γ-H2AX apoptotic ring, although morphologically distinct from the DNA damage response (DDR) focal pattern observed after DNA damage (28), also contains phosphorylated DDR proteins, including activated checkpoint kinase 2 (Chk2) (phosphorylated on T68), activated ataxia telangiectasia mutated (ATM) (phosphorylated on S1981), and activated DNA-PK itself (phosphorylated on T2609) (24)(25)(26). However, it lacks MDC1 and 53BP1 because of the caspase-induced cleavage of MDC1, which inactivates the initiation of DNA repair (25).…”

mentioning

confidence: 99%

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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: Hsp90α Phosphorylation Is An Extensive and Early Process Duringmentioning

confidence: 87%

Section: Hsp90α Phosphorylation Is An Extensive and Early Process Duringmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…TRAIL is a wellcharacterized proapoptotic agonist that activates a chain of caspases involved in apoptosis [105,106]. During apoptosis, γH2A.X staining initially localizes to a ring formation, followed by pan-nuclear staining at later times.…”

Section: H2ax and Programmed Cell Deathmentioning

confidence: 99%

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

2015

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The eukaryotic genome is highly complex and compartmentalized into distinct physical and functional domains. Although the majority of genomic DNA is wrapped around histone proteins in the same manner to form repeating units of nucleosomes, the use of distinct histone variants and the myriad of posttranslational modifications (PTMs) on different histones and amino acid residues create great diversity among these nucleosomes. In this review, we summarize some of the most recent findings in the histone variant and PTM fields and update the readers on our current understanding of various histone-related pathways. Furthermore, we discuss how homotypic or heterotypic deposition of histone variants as well as symmetric or asymmetric histone PTMs within the nucleosome context can further expand the diversity and functionality of chromatin. Altogether, this review highlights the complexity of chromatin composition and organization and their regulatory functions within the eukaryotic genome.

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Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

Tang,

Cui,

Liu

et al. 2024

Cancer Communications

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Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor‐associated macrophages (TAMs), myeloid‐derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy‐insensitive tumors into immunotherapy‐sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.

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The apoptotic ring: A novel entity with phosphorylated histones H2AX and H2B, and activated DNA damage response kinases

Cited by 110 publications

References 30 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

Chemical “Diversity” of Chromatin Through Histone Variants and Histone Modifications

Converting “cold” to “hot”: epigenetics strategies to improve immune therapy effect by regulating tumor‐associated immune suppressive cells

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