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Cited by 1,499DNA Repair MechanismsCRISPR and Genetic EngineeringPARP inhibition in cancer therapy

Repair Pathway Choices and Consequences at the Double-Strand Break

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Ceccaldi, Raphael, Rondinelli, Beatrice, D’Andrea, Alan D.·2016·Trends in Cell Biology
DOI 10.1016/j.tcb.2015.07.009PMC PMC4862604
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Abstract

DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate end-joining events, which commonly underlie oncogenic transformation due to chromosomal translocations. Typically, cells employ two main mechanisms to repair DSBs: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alternative error-prone DSB repair pathways, namely alternative end joining (alt-EJ) and single-strand annealing (SSA), have been recently shown to operate in many different conditions and to contribute to genome rearrangements and oncogenic transformation. Here, we review the mechanisms regulating DSB repair pathway choice, together with the potential interconnections between HR and the annealing-dependent error-prone DSB repair pathways.

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  • AhrTer383 arose as an apparent CRISPR-mediated NHEJ artifact during attempts to generate AhrV375A.

    “Like the AhrNG367R allele described above, the AhrTer383 mutant appears to have been generated as an artifact of CRISPR-mediated NHEJ during the effort to generate AhrV375A (Figure 5)(Ceccaldi et al., 2016; R. H. Wilson et al., 2021).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Ceccaldi et al., 2016

    The “Mechanisms of DNA DSB Repair” section describes classical NHEJ as a potentially mutagenic way to repair double-strand breaks, supporting the proposed repair mechanism in general. It does not discuss CRISPR editing, AhrTer383, or the attempt to generate AhrV375A, so it cannot support the allele-specific account. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Cas9-induced double-strand breaks repaired by NHEJ can cause unpredictable insertions or deletions.

    “It has been reported that unpredictable insertions or deletions may occur following a Cas9-induced double stranded break when the cell employs NHEJ to repair the double stranded break in the DNA (Ceccaldi et al., 2016).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Ceccaldi et al., 2016

    The “Annealing-Dependent DSB Repair Outcomes and Their Mutational Signatures” section (page unavailable) says alternative end joining can produce random insertions and deletions. The “Mechanisms of DNA DSB Repair” section distinguishes this pathway from classical NHEJ, and the copy does not establish that the reported indels follow Cas9-induced breaks. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The AhrNG367R mutant arose unintentionally via CRISPR-Cas9 while attempting to create AhrV375A from Ahrfx.

    “The AhrNG367R mutant was generated serendipitously using CRISPR-Cas9 during the attempt to generate the AhrV375A allele from the Ahrfx mouse described above (Figure 5) (Ceccaldi et al., 2016; R. H. Wilson et al., 2021).”

    From Rodent Genetic Models of Ah Receptor Signaling (2021) · cites this paper as Ceccaldi et al., 2016

    The passages on annealing-dependent double-strand-break repair and mutational signatures (pages unavailable) discuss repair mechanisms, not the generation of an Ahr mouse allele. Searches for AhrNG367R, AhrV375A, Ahrfx, and the described CRISPR-Cas9 attempt found no passage addressing the claim. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Ceccaldi, R., Rondinelli, B., & D’Andrea, A. D.
Affiliations
Harvard University (US)
Corresponding author
D’Andrea, Alan D.
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2016-01
Volume
26
Issue
1
Pages
52-64
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2015.07.009
PMC
PMC4862604
OpenAlex
W1841331176
Cited by
1,499
References
5
Citations by year
2026: 108 · 2025: 128 · 2024: 139 · 2023: 146 · 2022: 155 · 2021: 197 · 2020: 178 · 2019: 161 · 2018: 106 · 2017: 96 · 2016: 82 · 2015: 2
FWCI
9.29
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL052725)
  • National Cancer Institute (P50CA168504)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Keywords
DNA double-strand breaks, homologous recombination, alternative end-joining, single-strand annealing, error-prone DNA repair, genomic instability, chromosomal translocation, oncogenic transformation, genome rearrangement
MeSH terms
Animals, Cell Survival, DNA Repair, Humans, Mutation, Genomic Instability, DNA Breaks, Double-Stranded

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