Coordinated Activity of Y Family TLS Polymerases and EXO1 Protects Non-S Phase Cells from UV-Induced Cytotoxic Lesions
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UV-induced photoproducts are responsible for the pathological effects of sunlight. Mutations in nucleotide excision repair (NER) cause severe pathologies characterized by sunlight sensitivity, coupled to elevated predisposition to cancer and/or neurological dysfunctions. We have previously shown that in UV-irradiated non-cycling cells, only a particular subset of lesions activates the DNA damage response (DDR), and this requires NER and EXO1 activities. To define the molecular mechanism acting at these lesions, we demonstrate that Y family TLS polymerases are recruited at NER- and EXO1-positive lesion sites in non-S phase cells. The coordinated action of EXO1 and Y family TLS polymerases promotes checkpoint activation, leads to lesion repair, and is crucial to prevent cytotoxic double-strand break (DSB) formation.
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In eukaryotic cells, interaction of polymerases with PCNA, dependent on its ubiquitination status, seems crucial for employment of TLS polymerases for lesion bypass.
“In eukaryotic cells interaction of polymerases with PCNA (dependent on its ubiquitination status) seems to be crucial for employment of TLS polymerases for lesion bypass [127,129].”
From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [129]
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Xie, D., Huang, Q., & Zhou, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087656 · Cited by 6 · see citing works
Mammalian life depends on two distinct pathways of DNA damage tolerance
Buoninfante, O. A., Pilzecker, B., Spanjaard, A., de Groot, D., Preković, S., Song, J., Lieftink, C., Ayidah, M., Pritchard, C. E. J., Vivié, J., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2216055120 · Cited by 7 · see citing works
Discovery of ART5537: A Potent and Selective Small-Molecule Probe for EXO1
Mann, S. E., Davis, O. A., Bomke, J., Cornaciu, I., Elinati, E., Follows, B., Galbiati, A., Geo, L., Grande, D., Jorand‐Lebrun, C., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02593 · Cited by 4 · see citing works
Mandal, T., Shukla, D., Khan, M. M. A., Ganesan, S. K., & Srivastava, A. K. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02840-2 · Cited by 4 · see citing works
Understanding DNA and PARP in Cancer: Tackling Inhibitor Resistance
Balachandran, H., Byran, G., Karri, V. V. S. R., Murugesan, S. K., & Rajagopal, K. (2025) · Drug Metabolism and Bioanalysis Letters · doi:10.2174/0118723128343916250212094926 · Cited by 3 · see citing works
Recruitment and release of XPG during NER is controlled by pre- and post-incision factors and EXO1
Muniesa-Vargas, A., Ribeiro-Silva, C., Davó-Martínez, C., Raams, A., Geverts, B., van de Grint, J., Ganpat, M. M. P., Thijssen, K. L., Pothof, J., Houtsmuller, A. B., et al. (2026) · The Journal of Cell Biology · doi:10.1083/jcb.202602121 · Cited by 2 · see citing works
EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers
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Multiple Genotoxic Agents Activate ATR Kinase Signaling in Quiescent Human Cells
Madkhali, M. A. O. (2020) · CORE Scholar (Wright State University)
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Narimichi, M., Komaki, Y., Suzuki, T., & Ibuki, Y. (2026) · Photochemical & Photobiological Sciences · doi:10.1007/s43630-026-00874-4
DNA damage and repair: Future perspectives
Rajpurohit, Y. S., Mishra, A., Sharma, D. K., & Soni, I. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-42857-9.00002-5
- Authors
- Sertic, S., Mollica, A., Campus, I., Roma, S., Tumini, E., Aguilera, A., & Muzi-Falconi, M.
- Affiliations
- University of Milan (IT)
- Consejo Superior de Investigaciones Científicas (ES)
- Corresponding author
- Sertic, Sarah
- Muzi-Falconi, Marco
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 70
- Issue
- 1
- Pages
- 34-47.e4
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2790495781
- Cited by
- 45
- References
- 68
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 10 · 2019: 5 · 2018: 1
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-04-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Fondazione Umberto Veronesi
- AIRC (15631)
- Telethon (GGP15227)
- MIUR
- Spanish Ministry of Economy and Competitiveness (BFU2016-75058-P)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- EXO1, nucleotide excision repair, DNA damage response, double-strand break formation, DNA repair, checkpoint activation, UV sensitivity
- MeSH terms
- DNA Polymerase iota, Y-Family DNA Polymerases, Cell Line, DNA-Directed DNA Polymerase, DNA Repair, Exodeoxyribonucleases, Humans, Nuclear Proteins, Nucleotidyltransferases, Ultraviolet Rays, Cell Death, Protein Transport, DNA Repair Enzymes, DNA Breaks, Double-Stranded, Cell Cycle Checkpoints
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