UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and -independent pathways
Open accessAbstract
Activation of signaling pathways by UV radiation is a key event in the DNA damage response and initiated by different cellular processes. Here we show that non-cycling cells proficient in nucleotide excision repair (NER) initiate a rapid but transient activation of the damage response proteins p53 and H2AX; by contrast, NER-deficient cells display delayed but persistent signaling and inhibition of cell cycle progression upon release from G0 phase. In the absence of repair, UV-induced checkpoint activation coincides with the formation of single-strand DNA breaks by the action of the endonuclease Ape1. Although temporally distinct, activation of checkpoint proteins in NER-proficient and NER-deficient cells depends on a common pathway involving the ATR kinase. These data reveal that damage signaling in non-dividing cells proceeds via NER-dependent and NER-independent processing of UV photolesions through generation of DNA strand breaks, ultimately preventing the transition from G1 to S phase.
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H2AX phosphorylation upon UV radiation is triggered by both NER-dependent and independent pathways.
“Previous studies in this area showed that H2AX phosphorylation upon UV radiation is triggered by both NER-dependent and independent pathways [50;61–63].”
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 [62]
Vrouwe et al. reported that UV photolesions cause checkpoint activation through both NER-dependent and NER-independent routes.
“Furthermore, Vrouwe et al reported that UV-induced photolesions results in checkpoint activation in NER-dependent and -independent pathways [31].”
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 [31]
H2AX is phosphorylated at serine 139 (γH2AX) in the vicinity of ssDNA, single-strand breaks, and double-strand breaks.
“The variant histone H2AX is phosphorylated at serine 139 (forming ␥H2AX) in the vicinity of single-stranded DNA (ssDNA), DNA single-or double-strand breaks (SSBs and DSBs, respectively) [38][39][40].”
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 [39]
UVC irradiation induces γH2AX formation.
“Because UVC irradiation induces ␥H2AX formation [39][40][41][42][43]”
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 [39]
UV-induced signaling may proceed via NER-independent mechanisms in non-dividing mammalian cells, likely through DNA strand breaks.
“Recent evidence indicates that UV-induced signaling may proceed via NER-independent mechanisms also in non-dividing mammalian cells likely through generation of DNA strand breaks [97].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [97]
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References 74 · Cited by 100
- Authors
- Vrouwe, M. G., Pines, A., Overmeer, R. M., Hanada, K., & Mullenders, L. H. F.
- Affiliations
- Leiden University Medical Center (NL)
- Department of Toxicogenetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
- Erasmus MC (NL)
- Corresponding author
- Mullenders, Leon H. F.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2011-02-01
- Volume
- 124
- Issue
- 3
- Pages
- 435-446
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2133016391
- Cited by
- 100
- References
- 74
- Citations by year
- 2024: 4 · 2023: 6 · 2022: 5 · 2021: 9 · 2020: 7 · 2019: 7 · 2018: 15 · 2017: 5 · 2016: 9 · 2015: 4 · 2014: 6 · 2013: 6 · 2012: 11
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- ATR kinase, nucleotide excision repair, DNA damage response, p53, H2AX, APE1, single-strand breaks, cell cycle progression, DNA repair deficiency
- MeSH terms
- DNA Damage, DNA Repair, DNA, Single-Stranded, Histones, Humans, Ultraviolet Rays, Signal Transduction, Tumor Suppressor Protein p53, Resting Phase, Cell Cycle, Protein Serine-Threonine Kinases, Cell Cycle Proteins, DNA-(Apurinic or Apyrimidinic Site) Lyase, DNA Breaks, Single-Stranded, Ataxia Telangiectasia Mutated Proteins
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