Cited by 30DNA Repair MechanismsCarcinogens and Genotoxicity AssessmentSkin Protection and Aging

A Sensitive Flow Cytometry-based Nucleotide Excision Repair Assay Unexpectedly Reveals That Mitogen-activated Protein Kinase Signaling Does Not Regulate the Removal of UV-induced DNA Damage in Human Cells

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Rouget, Raphael, Auclair, Yannick, Loignon, Martin, Affar, El Bachir, Drobetsky, Elliot A.·2008·Journal of Biological Chemistry

Abstract

In response to diverse genotoxic stimuli (e.g. UV and cisplatin), the mitogen-activated protein kinases ERK1/2, JNK1/2, and p38alpha/beta become rapidly phosphorylated and in turn activate multiple downstream effectors that modulate apoptosis and/or growth arrest. Furthermore, previous lines of evidence have strongly suggested that ERK1/2 and JNK1/2 participate in global-genomic nucleotide excision repair, a critical antineoplastic pathway that removes helix-distorting DNA adducts induced by a variety of mutagenic agents, including UV. To rigorously evaluate the potential role of mitogen-activated protein kinases in global-genomic nucleotide excision repair, various human cell strains (primary skin fibroblasts, primary lung fibroblasts, and HCT116 colon carcinoma cells) were treated with highly specific chemical inhibitors, which, following UV exposure, (i) abrogated the capacities of ERK1/2, JNK1/2, or p38alpha/beta to phosphorylate specific downstream effectors and (ii) characteristically modulated cellular proliferation, clonogenic survival, and/or apoptosis. A highly sensitive flow cytometry-based nucleotide excision repair assay recently optimized and validated in our laboratory was then employed to directly demonstrate that the kinetics of UV DNA photoadduct repair are highly similar in mock-treated versus mitogen-activated protein kinase inhibitor-treated cells. These data on primary and tumor cells treated with pharmacological inhibitors were fully corroborated by repair studies using (i) short hairpin RNA-mediated knockdown of ERK1/2 or JNK1/2 in human U2OS osteosarcoma cells and (ii) expression of a dominant negative p38alpha mutant in human primary lung fibroblasts. Our results provide solid evidence for the first time, in disaccord with a burgeoning perception, that mitogen-activated protein kinase signaling does not influence the efficiency of human global-genomic nucleotide excision repair.

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  1. Mathonnet, G., Leger, C., Desnoyers, J., Drouin, R., Therrien, J. P., and Drobetsky, E. A. (2003) Proc. Natl. Acad. Sci. 100, 7219 -7224
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  6. Bennett, B. L., Sasaki, D. T., Murray, B. W., O'Leary, E. C., Sakata, S. T., Xu, W., Leisten, J. C., Motiwala, A., Pierce, S., Satoh, Y., Bhagwat, S. S., Manning, A. M., and Anderson, D. W. (2001) Proc. Natl. Acad. Sci. 98, 13681-13686

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Authors
Rouget, R., Auclair, Y., Loignon, M., Affar, E. B., & Drobetsky, E. A.
Affiliations
Hôpital Maisonneuve-Rosemont (CA)
Corresponding author
Drobetsky, Elliot A.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2008-02
Volume
283
Issue
9
Pages
5533-5541
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1995828394
Cited by
30
References
44
Citations by year
2024: 1 · 2023: 2 · 2022: 2 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 3 · 2012: 1
FWCI
0.66
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
  • Health Sciences › Medicine › Dermatology › Skin Protection and Aging
Keywords
nucleotide excision repair, MAPK signaling, UV-induced DNA damage, ERK1/2, JNK1/2, p38 MAPK, MAPK inhibitors, shRNA knockdown, clonogenic survival, apoptosis, cell proliferation, dermal fibroblasts, lung fibroblasts, colon cancer cells, osteosarcoma cells
MeSH terms
Cell Survival, DNA Damage, DNA Repair, Flow Cytometry, Humans, Phosphorylation, Ultraviolet Rays, Genome, Human, Apoptosis, DNA Adducts, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Mitogen-Activated Protein Kinase 11, Cell Proliferation

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