Benzo[a]pyrene induces complex H2AX phosphorylation patterns by multiple kinases including ATM, ATR, and DNA-PK

Yan, Chunxiao; Lü, Jing; Zhang, Guanglin; Gan, Tieer; Zeng, Qingze; Shao, Zongping; Duerksen-Hughes, Penelope J.; Yang, Jun

doi:10.1016/j.tiv.2010.09.012

Cited by 29 publications

(16 citation statements)

References 34 publications

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“…We could not re-capitulate the inhibitory effect of caffeine on GT using alternative approaches to perturb the DDR, and we did not observe the inhibition of ATM and ATR targets’ phosphorylation in the presence of caffeine in vivo (Figure 2). Consistent with our finding, a number of studies reports phosphorylation of ATM/ATR/DNA-PKcs substrates in the presence of millimolar concentrations of caffeine; most notably: Chk1 (39,81,82), RPA2 (83,84), Chk2 (82,85), as well as increased γH2AX in HeLa (86) and mouse ES cells (41). …”

Section: Discussionsupporting

confidence: 92%

Caffeine suppresses homologous recombination through interference with RAD51-mediated joint molecule formation

Zelensky

Sánchez

Ristić

et al. 2013

Nucleic Acids Research

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Caffeine is a widely used inhibitor of the protein kinases that play a central role in the DNA damage response. We used chemical inhibitors and genetically deficient mouse embryonic stem cell lines to study the role of DNA damage response in stable integration of the transfected DNA and found that caffeine rapidly, efficiently and reversibly inhibited homologous integration of the transfected DNA as measured by several homologous recombination-mediated gene-targeting assays. Biochemical and structural biology experiments revealed that caffeine interfered with a pivotal step in homologous recombination, homologous joint molecule formation, through increasing interactions of the RAD51 nucleoprotein filament with non-homologous DNA. Our results suggest that recombination pathways dependent on extensive homology search are caffeine-sensitive and stress the importance of considering direct checkpoint-independent mechanisms in the interpretation of the effects of caffeine on DNA repair.

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Section: Discussionsupporting

confidence: 92%

Caffeine suppresses homologous recombination through interference with RAD51-mediated joint molecule formation

Zelensky

Sánchez

Ristić

et al. 2013

Nucleic Acids Research

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“…This phosphorylation signaling is linked to formation of DSBs, but other types of DNA damage would also induce phosphorylation of these factors, for example oxidative DNA damage, formation of covalent DNA adducts, replication stress and SSBs. [62][63][64][65][66] This indicates that in latently infected cells, the DDR signaling pathway is activated in response to DNA damage suggesting that DNA repairs are not processed efficiently, or there is a factor raising the background level of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

et al. 2017

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Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells. These results indicate a DDR defect even though the virus is latent. DDR-inducing agents, specifically high doses of nucleoside RT inhibitors (NRTIs), caused greater increases in gamma-H2AX levels in latently infected cells. Additionally, latently infected cells are more susceptible to long-term exposure to G-quadruplex stabilizing agents, and this effect is enhanced when the agent is combined with an inhibitor targeting DNA-PK, which is crucial for DSB repair and telomere maintenance. Moreover, exposing these cells to the cancer drug etoposide resulted in formation of DSBs at a higher rate than in un-infected cells. Similar effects of etoposide were also observed in population of primary memory T cells infected with latent HIV-1. Sensitivity to these agents highlights a unique vulnerability of latently infected cells, a new feature that could potentially be used in developing therapies to eliminate HIV-1 reservoirs.

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“…Chemical and environmental agents that do not induce DSBs also could lead to H2AX phosphorylation. For example, the treatment of cells with chemical potent carcinogen benz[a]pyrene leads to formation of covalent DNA adducts that induce H2AX phosphorylation in ATM-, ATR-, and DNA-PK-dependent manner (Yan et al 2011). H2AX phosphorylation could be induced in DNA in the absence of DSBs by hyperthermia (Hunt et al 2007).…”

Section: Introductionmentioning

confidence: 99%

H2AX phosphorylation at the sites of DNA double-strand breaks in cultivated mammalian cells and tissues

2011

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A sequence variant of histone H2A called H2AX is one of the key components of chromatin involved in DNA damage response induced by different genotoxic stresses. Phosphorylated H2AX (γH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress. γH2AX foci could be easily detected in cell nuclei using immunofluorescence microscopy that allows to use γH2AX as a quantitative marker of DSBs in various applications. H2AX is phosphorylated in situ by ATM, ATR, and DNA-PK kinases that have distinct roles in different pathways of DSB repair. The γH2AX serves as a docking site for the accumulation of DNA repair proteins, and after rejoining of DSBs, it is released from chromatin. The molecular mechanism of γH2AX dephosphorylation is not clear. It is complicated and requires the activity of different proteins including phosphatases and chromatin-remodeling complexes. In this review, we summarize recently published data concerning the mechanisms and kinetics of γH2AX loss in normal cells and tissues as well as in those deficient in ATM, DNA-PK, and DSB repair proteins activity. The results of the latest scientific research of the low-dose irradiation phenomenon are presented including the bystander effect and the adaptive response estimated by γH2AX detection in cells and tissues.

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Benzo[a]pyrene induces complex H2AX phosphorylation patterns by multiple kinases including ATM, ATR, and DNA-PK

Cited by 29 publications

References 34 publications

Caffeine suppresses homologous recombination through interference with RAD51-mediated joint molecule formation

Caffeine suppresses homologous recombination through interference with RAD51-mediated joint molecule formation

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

H2AX phosphorylation at the sites of DNA double-strand breaks in cultivated mammalian cells and tissues

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