The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase
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Damaged DNA templates provide an obstacle to the replication fork and can cause genome instability. In eukaryotes, tolerance to damaged DNA is mediated largely by the RAD6 pathway involving ubiquitylation of the DNA polymerase processivity factor PCNA. Whereas monoubiquitylation of PCNA mediates error-prone translesion synthesis (TLS), polyubiquitylation triggers an error-free pathway. Both branches of this pathway are believed to occur in S phase in order to ensure replication completion. However, we found that limiting TLS or the error-free pathway to the G2/M phase of the cell-cycle efficiently promote lesion tolerance. Thus, our findings indicate that both branches of the DNA damage tolerance pathway operate effectively after chromosomal replication, outside S phase. We therefore propose that the RAD6 pathway acts on single-stranded gaps left behind newly restarted replication forks.
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In these conditions, repair may not be completed and ssDNA extension may both activate the checkpoint and channel the problematic lesion to another repair pathway such as recombination.
“In these conditions, repair may not be completed and the extension of the ssDNA region may meet two purposes: activating the checkpoint response and channeling the problematic lesion to a different repair pathway (e.g., recombination) [66–68].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [66]
S phase can be completed without PRR, but gapped replicated DNA must be refilled by PRR in G2 for cell survival.
“In fact, S phase can be completed in the absence of PRR, but the gapped replicated DNA needs to be refilled by PRR in G2 in order to warrant cell survival [66,67].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [66]
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Quinet, A., Vessoni, A. T., Rocha, C. R. R., Gottifredi, V., Biard, D., Sarasin, A., Menck, C. F. M., & Stary, A. (2014) · DNA Repair · doi:10.1016/j.dnarep.2013.12.005 · Cited by 70 · see citing works
Targeting the Translesion Synthesis Pathway for the Development of Anti-Cancer Chemotherapeutics
Korzhnev, D. M., & Hadden, M. K. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00596 · Cited by 58 · see citing works
Ziv, O., Zeisel, A., Mirlas-Neisberg, N., Swain, U., Nevo, R., Ben-Chetrit, N., Martelli, M. P., Rossi, R., Schiesser, S., Canman, C. E., et al. (2014) · Nature Communications · doi:10.1038/ncomms6437 · Cited by 59 · see citing works
Mind the gap: keeping UV lesions in check
Novarina, D., Amara, F., Lazzaro, F., Plevani, P., & Muzi-Falconi, M. (2011) · DNA Repair · doi:10.1016/j.dnarep.2011.04.030 · Cited by 43 · see citing works
Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage
Yang, Y., Durando, M., Smith-Roe, S. L., Sproul, C., Greenwalt, A. M., Kaufmann, W., Oh, S., Hendrickson, E. A., & Vaziri, C. (2013) · Nucleic Acids Research · doi:10.1093/nar/gks1325 · Cited by 33 · see citing works
The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight
Bertolin, A. P., Mansilla, S. F., & Gottifredi, V. (2015) · DNA Repair · doi:10.1016/j.dnarep.2015.04.027 · Cited by 30 · see citing works
Wigan, M., Pinder, A., Giles, N., Pavey, S., Burgess, A., Wong, S., Sturm, R. A., & Gabrielli, B. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.41 · Cited by 17 · see citing works
- Authors
- Karras, G. I., & Jentsch, S.
- Affiliations
- Max Planck Institute of Biochemistry (DE)
- Max Planck Society (DE)
- Corresponding author
- Jentsch, Stefan
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 141
- Issue
- 2
- Pages
- 255-267
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2059788298
- Cited by
- 282
- References
- 96
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 2 · 2023: 7 · 2022: 9 · 2021: 12 · 2020: 20 · 2019: 20 · 2018: 17 · 2017: 17 · 2016: 27 · 2015: 20 · 2014: 21 · 2013: 24 · 2012: 23
- FWCI
- 12.24
- 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, 1239 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
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- DNA damage tolerance, translesion synthesis, G2/M phase, S phase, replication fork restart, single-stranded DNA gaps, genomic instability, DNA polymerase processivity
- MeSH terms
- DNA Damage, DNA Repair, DNA Replication, DNA Helicases, Saccharomyces cerevisiae, S Phase, Proliferating Cell Nuclear Antigen, Saccharomyces cerevisiae Proteins, Ubiquitin-Conjugating Enzymes, RecQ Helicases, Metabolic Networks and Pathways, Ubiquitination
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