DNA damage bypass operates in the S and G2 phases of the cell cycle and exhibits differential mutagenicity
Open accessAbstract
Translesion DNA synthesis (TLS) employs low-fidelity DNA polymerases to bypass replication-blocking lesions, and being associated with chromosomal replication was presumed to occur in the S phase of the cell cycle. Using immunostaining with anti-replication protein A antibodies, we show that in UV-irradiated mammalian cells, chromosomal single-stranded gaps formed in S phase during replication persist into the G2 phase of the cell cycle, where their repair is completed depending on DNA polymerase ζ and Rev1. Analysis of TLS using a high-resolution gapped-plasmid assay system in cell populations enriched by centrifugal elutriation for specific cell cycle phases showed that TLS operates both in S and G2. Moreover, the mutagenic specificity of TLS in G2 was different from S, and in some cases overall mutation frequency was higher. These results suggest that TLS repair of single-stranded gaps caused by DNA lesions can lag behind chromosomal replication, is separable from it, and occurs both in the S and G2 phases of the cell cycle. Such a mechanism may function to maintain efficient replication, which can progress despite the presence of DNA lesions, with TLS lagging behind and patching regions of discontinuity.
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Polη ensures accurate replication of TT-CPDs, and its bypass may act at stalled replication forks and through post-replicative gap-filling.
“It is well established that Pol ensures accurate replication of TT-CPDs [21,22] and this bypass may act at the stalled replication fork [23,24] but also through a post-replicative gapfilling pathway [15,25].”
From Gap-filling and bypass at the replication fork are both active mechanisms for tolerance of low-dose ultraviolet-induced DNA damage in the human genome (2014) · cites this paper as [15]
Resolution of G2-phase arrest may be due to gap-filling mechanism involving TLS polymerase Rev1.
“the resolution of the G2-phase arrest observed may be due to the gap-filling mechanism involving the TLS polymerase Rev1 in this cell cycle phase, also in agreement with other reports [15,24]”
From Gap-filling and bypass at the replication fork are both active mechanisms for tolerance of low-dose ultraviolet-induced DNA damage in the human genome (2014) · cites this paper as [15]
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- Authors
- Diamant, N., Hendel, A., Vered, I., Carell, T., Reißner, T., de Wind, N., Geacinov, N., & Livneh, Z.
- Affiliations
- Leiden University Medical Center (NL)
- Corresponding author
- Livneh, Zvi
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-09-09
- Volume
- 40
- Issue
- 1
- Pages
- 170-180
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3245908
- OpenAlex
- W2088339455
- Cited by
- 109
- References
- 48
- Citations by year
- 2025: 2 · 2024: 9 · 2023: 10 · 2022: 2 · 2021: 9 · 2020: 6 · 2019: 7 · 2018: 6 · 2017: 13 · 2016: 8 · 2015: 8 · 2014: 7 · 2013: 8 · 2012: 13
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Flight Attendant Medical Research Institute
- National Cancer Institute
- National Institutes of Health
- 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 › Cancer Research › Carcinogens and Genotoxicity Assessment
- Keywords
- translesion synthesis, DNA damage bypass, S phase, G2 phase, cell cycle, UV-induced DNA damage, replication protein A, Rev1, mutagenesis, single-stranded DNA gaps, centrifugal elutriation, DNA replication
- MeSH terms
- Y-Family DNA Polymerases, Animals, Cells, Cultured, DNA, DNA Damage, DNA-Directed DNA Polymerase, DNA-Binding Proteins, Humans, Nuclear Proteins, Nucleotidyltransferases, Ultraviolet Rays, G2 Phase, S Phase, Mutagenesis, Cell Line, Tumor, Mice, Replication Protein A
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