Human exonuclease 1 connects nucleotide excision repair (NER) processing with checkpoint activation in response to UV irradiation
Open accessAbstract
UV light induces DNA lesions, which are removed by nucleotide excision repair (NER). Exonuclease 1 (EXO1) is highly conserved from yeast to human and is implicated in numerous DNA metabolic pathways, including repair, recombination, replication, and telomere maintenance. Here we show that hEXO1 is involved in the cellular response to UV irradiation in human cells. After local UV irradiation, fluorescent-tagged hEXO1 localizes, together with NER factors, at the sites of damage in nonreplicating cells. hEXO1 accumulation requires XPF-dependent processing of UV-induced lesions and is enhanced by inhibition of DNA repair synthesis. In nonreplicating cells, depletion of hEXO1 reduces unscheduled DNA synthesis after UV irradiation, prevents ubiquitylation of histone H2A, and impairs activation of the checkpoint signal transduction cascade in response to UV damage. These findings reveal a key role for hEXO1 in the UV-induced DNA damage response linking NER to checkpoint activation in human cells.
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ATR/ATM is recruited to the NER processed long ssDNA where EXO1 binds.
“and therefore it is highly likely that ATR/ATM is recruited to the NER processed long ssDNA where EXO1 binds [46].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [46]
In G1, checkpoint activation is due to ssDNA and not from DSBs.
“Previous studies showed that in G1, checkpoint activation is due to the ssDNA and not from DSBs [33;46;49]”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [46]
hEXO1 association to NER processed ssDNA is restricted to non-replicating cells and is needed for checkpoint activation in G1.
“Additionally, Sertic et. al. also found that hEXO1 association to NER processed ssDNA is restricted to non-replicating cells, and is needed for checkpoint activation in G1 [46].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [46]
Several studies have reported that NER factor-mediated lesion processing might be required for γH2AX foci formation.
“However, several studies reported that lesion processing by NER factors might be an essential step in γH2AX foci formation [35-39].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [39]
Exo1 localizes with XPA at damage sites after local UV irradiation in non-replicating cells and converts NER intermediates into single-stranded DNA to promote DDR signaling.
“Exo1 localizes with XPA to damage sites after local UV irradiation in non-replicating cells and converts NER intermediates into ssDNA to promote DDR signaling [99, 205]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [205]
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- Authors
- Sertic, S., Pizzi, S., Cloney, R., Lehmann, A. R., Marini, F., Plevani, P., & Muzi-Falconi, M.
- Affiliations
- University of Milan (IT)
- University of Sussex (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-08
- Volume
- 108
- Issue
- 33
- Pages
- 13647-13652
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3158162
- OpenAlex
- W2040992769
- Cited by
- 80
- References
- 33
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 8 · 2016: 10 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 5
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- Funders
- European Commission (512113)
- Fondazione Cariplo
- Medical Research Council
- 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, UV irradiation, DNA damage response, DNA damage checkpoint, unscheduled DNA synthesis
- MeSH terms
- Cell Line, DNA Damage, DNA Repair, Exodeoxyribonucleases, Histones, Humans, Ultraviolet Rays, Cell Cycle Proteins, DNA Repair Enzymes, Ubiquitination
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