Coupling of Human DNA Excision Repair and the DNA Damage Checkpoint in a Defined in Vitro System
Open accessAbstract
DNA repair and DNA damage checkpoints work in concert to help maintain genomic integrity. In vivo data suggest that these two global responses to DNA damage are coupled. It has been proposed that the canonical 30 nucleotide single-stranded DNA gap generated by nucleotide excision repair is the signal that activates the ATR-mediated DNA damage checkpoint response and that the signal is enhanced by gap enlargement by EXO1 (exonuclease 1) 5' to 3' exonuclease activity. Here we have used purified core nucleotide excision repair factors (RPA, XPA, XPC, TFIIH, XPG, and XPF-ERCC1), core DNA damage checkpoint proteins (ATR-ATRIP, TopBP1, RPA), and DNA damaged by a UV-mimetic agent to analyze the basic steps of DNA damage checkpoint response in a biochemically defined system. We find that checkpoint signaling as measured by phosphorylation of target proteins by the ATR kinase requires enlargement of the excision gap generated by the excision repair system by the 5' to 3' exonuclease activity of EXO1. We conclude that, in addition to damaged DNA, RPA, XPA, XPC, TFIIH, XPG, XPF-ERCC1, ATR-ATRIP, TopBP1, and EXO1 constitute the minimum essential set of factors for ATR-mediated DNA damage checkpoint response.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NER recruits ATR to UV-damage sites and activates ATR in G1 phase but not in S phase.
“Consistently, NER recently was found to recruit ATR to the UV-damage sites and to activate ATR in G1-phase but not in S-phase 73–76.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [75]
H2AX phosphorylation upon UV radiation is triggered by both NER-dependent and independent pathways.
“Previous studies in this area showed that H2AX phosphorylation upon UV radiation is triggered by both NER-dependent and independent pathways [50;61–63].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [63]
ATR is critical for UV DNA damage signaling and is linked with NER.
“ATR (ATM and Rad3-related) is critical to UV DNA damage signaling (Ciccia and Elledge, 2010) and is intimately linked with NER”
From RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage (2014) · cites this paper as Lindsey-Boltz et al., 2014
Exo1 functionally couples the NER and ATR signaling pathways.
“indicating that NER and ATR signaling pathways are functionally coupled by Exo1 [206]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [206]
In a biochemically defined system, enlargement of gaps by Exo1 is required for ATR-Chk1 checkpoint activation.
“it was shown in a biochemically defined system that the gap enlargement by Exo1 is essential for ATR-Chk1 checkpoint activation”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [206]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 65 · Cited by 59
- Authors
- Lindsey-Boltz, L. A., Kemp, M. G., Reardon, J. T., DeRocco, V., Iyer, R. R., Modrich, P., & Sancar, A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Duke Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sancar, Aziz
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 289
- Issue
- 8
- Pages
- 5074-5082
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3931066
- OpenAlex
- W1968765462
- Cited by
- 59
- References
- 65
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 8 · 2016: 10 · 2015: 15 · 2014: 8 · 2013: 1
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (P30CA014236)
- National Institute of General Medical Sciences (R01GM032833, GM 45190, GM32833, R01GM045190)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- nucleotide excision repair, DNA damage checkpoint, ATR kinase, single-stranded DNA gaps, checkpoint signaling, RPA, XPC, XPG, TFIIH, TopBP1, UV-induced DNA damage
- MeSH terms
- Animals, DNA, DNA Damage, DNA Repair, Exodeoxyribonucleases, Humans, Kinetics, Models, Biological, Phosphorylation, Signal Transduction, Tumor Suppressor Protein p53, Mice, Replication Protein A, Ataxia Telangiectasia Mutated Proteins
About these checks
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 ›
Are you an author, or do you see a problem with this page? Request a review
