γH2AX foci formation in the absence of DNA damage: Mitotic H2AX phosphorylation is mediated by the DNA‐PKcs/CHK2 pathway

Tu, Wenzhi; Li, Bing; Huang, Bo; Wang, Yu; Liu, Xiaodan; Guan, Hua; Zhang, Shimeng; Tang, Yan; Rang, Wei-Qing; Zhou, Ping‐Kun

doi:10.1016/j.febslet.2013.08.028

Cited by 122 publications

(113 citation statements)

References 37 publications

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“…It should be noted, however, that H2AX phosphorylation does not always depend on DSBs, e.g., it may by induced by hypoxia 37 or in cell cycle-dependent manner in mitosis. [25][26][27] We find, however, that inducing new DSBs by NCS results in a concentration-dependent increase in gH2AX/MDC1 foci in GVstage oocytes. This increase correlates with the increase in chromosome segregation errors (mainly chromosome fragments) during anaphase I and thus suggests that these foci are a reliable means to estimate DSBs in GV-stage oocytes.…”

Section: Discussionmentioning

confidence: 62%

“…6 However, during mitosis gH2AX does not form foci but rather spreads over the condensed chromosomes and H2AX phosphorylation increases in PIKKs (ATM, DNA-PKcs)-dependent manner even in the absence of exogenous DNA damage. 25,27 In oocytes we find that H2AX phosphorylation increases after resumption of meiosis in a cell -cycle dependent manner: it reaches a maximum at MI and then decreases by MII. Our data indicate that H2AX phosphorylation in MI is ATM-independent, which is in agreement with low ATM expression and activation in mouse oocytes, 14 and that MRE11 and ATR, not ATM, are involved in cell-cycle dependent regulation of H2AX phosphorylation in MI.…”

Section: Discussionmentioning

confidence: 86%

“…This suggestion is consistent with the finding that in somatic cells H2AX is phosphorylated during mitosis in cell cycle-dependent but DNA damage-independent manner. [25][26][27] Most importantly, the decrease in the number of both endogenous and NCSinduced gH2AX foci between GV-stage and MII implies that DNA repair or other DNA processes, such as DNA break tethering, occur during meiotic maturation.…”

Section: H2ax Phosphorylation Changes During Meiotic Maturation and Pmentioning

confidence: 99%

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DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by gH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 86%

Section: H2ax Phosphorylation Changes During Meiotic Maturation and Pmentioning

confidence: 99%

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DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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“…20,21,23,25,41,42 Although incapability of mounting a complete DDR during mitosis could be due to chromatin condensation, one must consider that irradiation during mitosis is able to induce H2AX phosphorylation 18,43 and recruitment of some other signaling and repair factors, 44 thus, being able to access the condensed chromatin and start loading a DDR. The results presented here demonstrate that all gH2AX foci, those that co-localize with breaks, and those located at sites of apparently intact chromatin, strictly co-localize with MRE11 foci.…”

Section: Discussionmentioning

confidence: 99%

γH2AX foci on apparently intact mitotic chromosomes: Not signatures of misrejoining events but signals of unresolved DNA damage

et al. 2014

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Abbreviations: AU, arbitrary units; DSB, DNA double-strand break; FISH, fluorescence in situ hybridization; IRIF, ionizing radiation induced foci; FI, fluorescence intensity; mFISH, multicolor fluorescence in situ hybridization; MRN complex, MRE11-Rad50-Nbs1 complex; SD, standard deviation; TIF, telomere-dysfunction induced foci.The presence of gH2AX foci on apparently intact mitotic chromosomes is controversial because they challenge the assumed relationship between gH2AX foci and DNA double-strand breaks (DSBs). In this work, we show that after irradiation during interphase, a variety of gH2AX foci are scored in mitotic cells. Surprisingly, approximately 80% of the gH2AX foci spread over apparently undamaged chromatin at Terminal or Interstitial positions and they can display variable sizes, thus being classified as Small, Medium and Big foci. Chromosome and chromatid breaks that reach mitosis are spotted with Big (60%) and Medium (30%) Terminal gH2AX foci, but very rarely are they signaled with Small gH2AX foci. To evaluate if Interstitial gH2AX foci might be signatures of misrejoining, an mFISH analysis was performed on the same slides. The results show that Interstitial gH2AX foci lying on apparently intact chromatin do not mark sites of misrejoining, and that misrejoined events were never signaled by a gH2AX foci during mitosis. Finally, when analyzing the presence of other DNA-damage response (DDR) factors we found that all gH2AX foci-regardless their coincidence with a visible break-always colocalized with MRE11, but not with 53BP1. This pattern suggests that these gH2AX foci may be hallmarks of both microscopically visible and invisible DNA damage, in which an active, although incomplete or halted DDR is taking place.

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“…A representative γH2AX staining is shown in Figure 2a. The cut-off level of 20% was chosen, because the phosphorylation of H2AX at Ser-139 is also reported to occur during the S and G 2 /M phase in the cell cycle (15), and because the normal tonsil nuclei, which served as positive controls, showed <20% γH2AX positivity (data not shown). Thus, the γH2AX levels were low in 24 patients (58.5%) and high in 17 patients (41.5%).…”

Section: γH2ax Expression and Its Relationship With Pd-l1mentioning

confidence: 99%

The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma

Osoegawa

Hiraishi

Hashimoto

et al. 2018

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Abstract. Background Lung cancer, which is a leading cause of cancer death worldwide, is associated with a poor survival, even when the tumor is surgically removed. In terms of histology, lung squamous cell carcinoma, which accounts for 22% of the cases of resected lung cancer, is associated with poorer overall survival, with a five-year survival rate of approximately 60% in comparison to adenocarcinoma, which is the most common histological type (68%) and which has a five-year survival rate of approximately 75% (1). Molecular targeting therapies have recently been developed and have shown promising results against advanced lung cancer. Among the various types of lung cancer, lung squamous cell carcinoma has fewer treatment options because it is driven by alterations of tumor suppressor genes and subsequent chromosomal instability rather than oncogenic mutations (2). The chromosomal instability results in accumulation of somatic mutations and DNA damage response (3). This may explain why carcinogen-induced cancer, like lung squamous cell carcinoma and melanoma, is often accompanied by inflammation, as the DNA damage response is a major trigger activating the innate immune response. This consequence has been closely examined in the immune elimination process during viral infection and recently in the cancer immunity cycle (4).The activation of the innate immune response leads to activation of immune checkpoint molecules as a mechanism of immune escape. Programmed death-ligand 1 (PD-L1) is one of the immune checkpoint molecules that are expressed on the surface of tumor cells. Once it is expressed on the tumor cells, PD-L1 binds to its receptor, PD-1, on the membrane of the cytotoxic T cell and inhibits T cell activity, resulting in the escape of the tumor cell from the immune system (5). The recent development of therapies against immune checkpoint molecules, namely, CTLA-4, PD-1 and PD-L1 has shown that PD-1/PD-L1 blockade can improve overall survival in patients with cancer including malignant melanoma, lung squamous cell carcinoma, and lung adenocarcinoma (6-13).During the DNA damage response process, γH2AX, a unique histone subunit, serves as a sensor of double-stranded DNA damage, thereby gathering other proteins to form DNA damage repair complex foci (14). γH2AX foci are formed through irradiation, UV exposure, and cytotoxic chemotherapy, and the overexpression of γH2AX is common among various types of cancer. We hypothesized that the 171 This article is freely accessible online.Correspondence to: Ass. Prof.

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γH2AX foci formation in the absence of DNA damage: Mitotic H2AX phosphorylation is mediated by the DNA‐PKcs/CHK2 pathway

Cited by 122 publications

References 37 publications

DNA damage response during mouse oocyte maturation

DNA damage response during mouse oocyte maturation

γH2AX foci on apparently intact mitotic chromosomes: Not signatures of misrejoining events but signals of unresolved DNA damage

The Positive Relationship Between γH2AX and PD-L1 Expression in Lung Squamous Cell Carcinoma

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