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Mutagenic Capacity of Endogenous G4 DNA Underlies Genome Instability in FANCJ-Defective C. elegans
Open accessAbstract
To safeguard genetic integrity, cells have evolved an accurate but not failsafe mechanism of DNA replication. Not all DNA sequences tolerate DNA replication equally well [1]. Also, genomic regions that impose structural barriers to the DNA replication fork are a potential source of genetic instability [2, 3]. Here, we demonstrate that G4 DNA-a sequence motif that folds into quadruplex structures in vitro [4, 5]-is highly mutagenic in vivo and is removed from genomes that lack dog-1, the C. elegans ortholog of mammalian FANCJ [6, 7], which is mutated in Fanconi anemia patients [8-11]. We show that sequences that match the G4 DNA signature G3-5N1-3G3-5N1-3G3-5N1-3G3-5 are deleted in germ and somatic tissues of dog-1 animals. Unbiased aCGH analyses of dog-1 genomes that were allowed to accumulate mutations in >100 replication cycles indicate that deletions are found exclusively at G4 DNA; deletion frequencies can reach 4% per site per animal generation. We found that deletion sizes fall short of Okazaki fragment lengths [12], and no significant microhomology was observed at deletion junctions. The existence of 376,000 potentially mutagenic G4 DNA sites in the human genome could have major implications for the etiology of hereditary FancJ and nonhereditary cancers.
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“In particular, FANCJ, similar to the Caenorhabditis elegans dog-1 ortholog, functions to resolve DNA structures that interfere with DNA replication, such as guanine quadriduplex (G4-DNA) structures [78].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [78]
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The tailless ortholog nhr-67 functions in the development of the C. elegans ventral uterus
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Metadata
- Authors
- Kruisselbrink, E., Guryev, V., Brouwer, K., Pontier, D. B., Cuppen, E., & Tijsterman, M.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- Corresponding author
- Tijsterman, Marcel
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 18
- Issue
- 12
- Pages
- 900-905
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2100493498
- Cited by
- 209
- References
- 26
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 14 · 2023: 7 · 2022: 14 · 2021: 18 · 2020: 14 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 15 · 2015: 15 · 2014: 17 · 2013: 6 · 2012: 6
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1872 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- ZonMw
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- G4 DNA, DNA quadruplex, mutagenesis, genomic instability, FANCJ, TMEM16A, Fanconi anemia, DNA replication, deletion hotspots, Okazaki fragments, microhomology, Caenorhabditis elegans, hereditary cancer, array comparative genomic hybridization
- MeSH terms
- Animals, Base Sequence, DNA Replication, DNA Helicases, Mutation, Nucleic Acid Hybridization, Caenorhabditis elegans, Sequence Deletion, Sequence Analysis, DNA, Oligonucleotide Array Sequence Analysis, Caenorhabditis elegans Proteins, Genomic Instability, Basic-Leucine Zipper Transcription Factors, Fanconi Anemia Complementation Group Proteins, G-Quadruplexes
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