Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress

Shan, Yan Shen; Sorrell, Melanie; Berman, Zachary

doi:10.1007/s00018-014-1666-4

Cited by 191 publications

(177 citation statements)

References 219 publications

(212 reference statements)

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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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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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“…xidative stress is the imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses (1,2). This presents a major challenge to genomic stability (3)(4)(5)(6) and is implicated in the pathogenesis of multiple human diseases, including cancer and neurodegenerative disorders (7,8).…”

mentioning

confidence: 99%

“…This presents a major challenge to genomic stability (3)(4)(5)(6) and is implicated in the pathogenesis of multiple human diseases, including cancer and neurodegenerative disorders (7,8). Abundant DNA damage from oxidative stress constitutes ∼10% of all DNA lesions and includes oxidative DNA damage, such as base damage, sugar moiety damage, apurinic/apyrimidinic (AP) sites, DNA single-strand breaks (SSBs), and double-strand breaks (DSBs) (2,6). Repair of oxidative lesions involves primarily the base excision repair (BER) pathway (9,10).…”

mentioning

confidence: 99%

“…Chk1 phosphorylation serves as an indicator of ATR activation, and activated Chk1 kinase phosphorylates its own substrates, such as Cdc25, to arrest cell cycle progression (20,21). We recently established that the ATR-Chk1 checkpoint is triggered by oxidative DNA damage in Xenopus egg extracts (2,22). Here, checkpoint activation critically requires the APE2 (apurinic/ apyrimidinic endonuclease 2) 3′-5′ resection nuclease.…”

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confidence: 99%

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APE2 Zf-GRF facilitates 3′-5′ resection of DNA damage following oxidative stress

Wallace

Berman

Mueller

et al. 2016

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

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104

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The Xenopus laevis APE2 (apurinic/apyrimidinic endonuclease 2) nuclease participates in 3′-5′ nucleolytic resection of oxidative DNA damage and activation of the ATR-Chk1 DNA damage response (DDR) pathway via ill-defined mechanisms. Here we report that APE2 resection activity is regulated by DNA interactions in its Zf-GRF domain, a region sharing high homology with DDR proteins Topoisomerase 3α (TOP3α) and NEIL3 (Nei-like DNA glycosylase 3), as well as transcription and RNA regulatory proteins, such as TTF2 (transcription termination factor 2), TFIIS, and RPB9. Biochemical and NMR results establish the nucleic acid-binding activity of the Zf-GRF domain. Moreover, an APE2 Zf-GRF X-ray structure and small-angle X-ray scattering analyses show that the Zf-GRF fold is typified by a crescent-shaped ssDNA binding claw that is flexibly appended to an APE2 endonuclease/exonuclease/phosphatase (EEP) catalytic core. Structure-guided Zf-GRF mutations impact APE2 DNA binding and 3′-5′ exonuclease processing, and also prevent efficient APE2-dependent RPA recruitment to damaged chromatin and activation of the ATR-Chk1 DDR pathway in response to oxidative stress in Xenopus egg extracts. Collectively, our data unveil the APE2 Zf-GRF domain as a nucleic acid interaction module in the regulation of a key single-strand break resection function of APE2, and also reveal topologic similarity of the Zf-GRF to the zinc ribbon domains of TFIIS and RPB9.oxidative stress | APE2 | Zf-GRF | crystallography | Xenopus laevis

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“…Recent studies have shown that the prodrug scaffold is cleaved off during the conversion of precolibactin to colibactin [31,32]. Colibactin could act indirectly, for example, by inducing oxidative stress that triggers the release of free radicals reacting with DNA strands [33]. However, ROS are not immediately detected after infection, but rather a couple of days later [21], suggesting the early action of other factors, possibly nuclease(s).…”

Section: E Coli At the Gut Microbiota Scalementioning

confidence: 99%

When our genome is targeted by pathogenic bacteria

Lemercier

2015

Cell. Mol. Life Sci.

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Eukaryotic cells repair thousands of lesions arising in the genome at each cell cycle. The most hazardous damage is likely DNA doublestrand breaks (DSB) that cleave the double helix backbone. DSBs occur naturally during T-cell receptor and immunoglobulin gene recombination in lymphocytes. DSBs can also arise as a consequence of exogenous stresses (e.g. ionizing irradiation, chemotherapeutic drugs, viruses) or oxidative processes. An increasing number of studies have reported that infection with pathogenic bacteria also alters the host genome, producing DSB and other modifications on DNA. This review focuses on recent data on bacteria-induced DNA damage and the known strategies used by these pathogens to maintain a physiological niche in the host. Even after DNA repair in infected cells, "scars" often remain on chromosomes and might generate genomic instability at the next cell division. Chronic inflammation in tissue, combined with infection and DNA damage, can give rise to genomic instability and eventually cancer. A functional link between the DNA damage response and the innate immune response has been recently established. Pathogenic bacteria also highjack the host cell cycle, often acting on the stability of the master regulator p53, or dampen the DNA damage response to support bacterial replication in an appropriate reservoir. Except in a few cases, the molecular mechanisms responsible for DNA lesions are poorly understood, although ROS release during infection is a serious candidate for generating DNA breaks. Thus, chronic or repetitive infections with genotoxic bacteria represent a common source of DNA lesions that compromise host genome integrity.

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Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress

Cited by 191 publications

References 219 publications

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

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

APE2 Zf-GRF facilitates 3′-5′ resection of DNA damage following oxidative stress

When our genome is targeted by pathogenic bacteria

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