APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress
Open accessAbstract
The base excision repair pathway is largely responsible for the repair of oxidative stress-induced DNA damage. However, it remains unclear how the DNA damage checkpoint is activated by oxidative stress at the molecular level. Here, we provide evidence showing that hydrogen peroxide (H 2 O 2 ) triggers checkpoint kinase 1 (Chk1) phosphorylation in an ATR [ataxia-telangiectasia mutated (ATM) and Rad3-related]-dependent but ATM-independent manner in Xenopus egg extracts. A base excision repair protein, Apurinic/apyrimidinic (AP) endonuclease 2 (APE2, APN2, or APEX2), is required for the generation of replication protein A (RPA)-bound single-stranded DNA, the recruitment of a checkpoint protein complex [ATR, ATR-interacting protein (ATRIP), and Rad9] to damage sites, and H 2 O 2 -induced Chk1 phosphorylation. A conserved proliferating cell nuclear antigen interaction protein box of APE2 is important for the recruitment of APE2 to H 2 O 2 -damaged chromatin. APE2 3′-phosphodiesterase and 3′-5′ exonuclease activity is essential for single-stranded DNA generation in the 3′–5′ direction from single-stranded breaks, referred to as single-stranded break end resection. In addition, APE2 associates with Chk1, and a serine residue (S86) in the Chk1-binding motif of APE2 is essential for Chk1 phosphorylation, indicating a Claspin-like but distinct role for APE2 in ATR-Chk1 signaling. Our data indicate that APE2 plays a vital and previously unexpected role in ATR-Chk1 checkpoint signaling in response to oxidative stress. Thus, our findings shed light on a distinct mechanism of how an ATR-Chk1–dependent DNA damage checkpoint is mediated by APE2 in the oxidative stress response.
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Long single-stranded DNA can be generated by uncoupling MCM helicase and DNA polymerase during replication stress, by CtIP-mediated double-strand break end resection, by Exo1-mediated processing of nucleotide excision repair intermediates after UV, and by APE2-mediated single-strand break end resection in oxidative stress.
“A long stretch of ssDNA can be generated through the functional uncoupling of minichromosome maintenance (MCM) helicase and DNA polymerase in DNA replication stress, the DSB end resection by DNA exonuclease such as CtIP in DSB response, the Exo1-mediated processing of NER intermediates after UV radiation, and the SSB end resection by AP endonuclease 2 (APE2) in oxidative stress [86, 97–99]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
Chk1 is phosphorylated at serine 345 by ATR in response to stalled DNA replication forks and DNA damage induced by UV, ionizing radiation, methyl methanesulfonate, mitomycin C, and hydrogen peroxide.
“As a critical player in DDR, Chk1 is phosphorylated at Serine 345 by ATR in response to stalled DNA replication forks and DNA damage induced by UV, IR, methyl methanesulfonate (MMS), mitomycin C (MMC), and hydrogen peroxide [85–90].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
Hydrogen peroxide triggers both ATM phosphorylation at serine 1981 and Chk1 phosphorylation at serine 344 in Xenopus egg extracts.
“Hydrogen peroxide triggers both ATM phosphorylation at Serine 1981 and Chk1 phosphorylation at Serine 344 in Xenopus egg extracts [86].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
Eliminating ATM kinase activity with KU55933 does not affect hydrogen peroxide-induced Chk1 phosphorylation, suggesting ATM may be nonessential for ATR-Chk1 checkpoint activation in oxidative stress.
“However, eliminating ATM kinase activity by its specific inhibitor KU55933 does not affect hydrogen peroxide-induced Chk1 phosphorylation, suggesting ATM may be nonessential for ATR-Chk1 checkpoint activation in oxidative stress response [86].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
Hydrogen peroxide triggers ATR-Chk1 checkpoint signaling in human dermal fibroblasts HDF cells and in Xenopus egg extracts.
“More recently, it has been demonstrated that hydrogen peroxide triggers ATR-Chk1 checkpoint signaling in human dermal fibroblasts HDF cells [137] and in Xenopus egg extracts [86].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
APE2 is needed to recruit ATR, ATRIP, and the 9-1-1 complex onto RPA-coated single-stranded DNA.
“APE2 is required for the recruitment of key checkpoint proteins including ATR, ATRIP, and the 9-1-1 complex onto RPA-ssDNA.”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
APE2 interacts with Chk1 and delivers Chk1 to activated ATR for phosphorylation.
“APE2 associates with Chk1 and brings Chk1 to activated ATR for phosphorylation [86]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
Recruitment of the 9-1-1 complex to H2O2-damaged chromatin requires APE2-mediated generation of RPA-coated single-stranded DNA, suggesting that the 9-1-1 complex may promote BER through a positive feedback mechanism.
“Importantly, the recruitment of the 9-1-1 complex to H2O2-damaged chromatin requires APE2-mediated generation of RPA-ssDNA, suggesting the 9-1-1 complex may promote the BER pathway via a positive feedback mechanism [86].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
The BER protein APE2 has several essential functions in ATR-Chk1 checkpoint signaling during oxidative stress.
“a BER protein APE2 plays several essential roles for ATR-Chk1 checkpoint signaling during oxidative stress [86]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
APE2 binds chromatin damaged by hydrogen peroxide and resects single-strand breaks in the 3' to 5' direction using its 3'-phosphodiesterase and 3' to 5' exonuclease activities, producing RPA-coated single-stranded DNA.
“APE2 binds to hydrogen peroxide-damaged chromatin and resects the SSB in the 3′–5′ direction via its 3′-phosphodiesterase and 3′–5′ exonuclease activities, generating RPA-ssDNA.”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [86]
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Self-citation
- Authors
- Willis, J., Patel, Y., Lentz, B. L., & Yan, S.
- Affiliations
- University of North Carolina at Charlotte (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-06-10
- Volume
- 110
- Issue
- 26
- Pages
- 10592-10597
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3696815
- OpenAlex
- W2011777722
- Cited by
- 100
- References
- 73
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 9 · 2017: 4 · 2016: 9 · 2015: 5 · 2014: 16 · 2013: 2
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R15GM101571)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- APE2, ATR-Chk1 signaling, DNA damage checkpoint, oxidative stress, hydrogen peroxide, base excision repair, RPA, ATRIP, Rad9, Claspin, Chk1 phosphorylation, 3'-5' exonuclease activity, DNA repair
- MeSH terms
- Checkpoint Kinase 1, Amino Acid Sequence, Animals, Cell-Free System, DNA Damage, DNA Repair, DNA, Single-Stranded, Female, Hydrogen Peroxide, Molecular Sequence Data, Ovum, Phosphorylation, Protein Kinases, Recombinant Proteins, Xenopus laevis, Signal Transduction, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Oxidative Stress, Cell Cycle Proteins, Xenopus Proteins, DNA-(Apurinic or Apyrimidinic Site) Lyase, Ataxia Telangiectasia Mutated Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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