DNA damage induces phosphorylation of the amino terminus of p53
Open accessAbstract
Data are presented demonstrating that DNA damage leads to specific post-translational modifications of p53 protein. Using two-dimensional peptide mapping of in vivo radiolabeled p53 tryptic phosphopeptides, recombinant truncated p53 protein, and synthetic p53 tryptic peptides, a unique p53 phosphopeptide was identified after exposure of ML-1 cells to ionizing irradiation. This peptide represents the first 24 amino acids of p53 and contains three phosphorylated serine residues. A specific p53 phosphopeptide antibody identified serine-15 as one of the two serines in p53 that becomes phosphorylated following DNA damage induced by either ionizing irradiation (IR) or ultraviolet (UV) irradiation in multiple cell types. IR-induced phosphorylation of p53 does not affect the kinetics of p53 binding to or dissociating from DNA as assessed by electrophoretic mobility-shift assays. However, p53 phosphorylation induced by DNA damage correlates with enhanced transcription of downstream p53 target genes. Low levels of phosphoserine-15 p53 are detectable within 6 hr after IR in AT cells, whereas lymphoblasts from normal individuals exhibit this modification within 1 hr. In contrast, phosphorylation of p53 on serine-15 is similar in normal and AT cells after UV irradiation. Our results indicate that p53 is phosphorylated in response to DNA damage, that this de novo phosphorylation may be involved in the subsequent induction and activation of p53, and that although ATM affects the kinetics of p53 phosphorylation after IR, it is not absolutely required for phosphorylation of p53 on serine-15.
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Five of five early generation mTerc Ink4a/Arf-/- tumor cell lines maintained intact p53 response after doxorubicin treatment, evidenced by p53 Ser-18 phosphorylation and associated induction of p21CIP1.
“Doxorubicin treatment of early passage tumor cell lines revealed that five of five early generation mTerc Ink4a / Arf -/ -tumors maintained intact p53 response evidenced by p53 Ser-18 phosphorylation (37, 38) and associated induction of p21 CIP1 .”
From <i>Ink4a</i> / <i>Arf</i> tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [38]
The paper’s ‘Ionizing irradiation induces phosphorylation of p53 on serine-15’ section reports DNA-damage-induced phosphorylation of human p53; its introductory discussion identifies human Ser-15 as corresponding to mouse Ser-18. It also reports p21 induction after irradiation. It does not establish Ser-18 phosphorylation after doxorubicin in the specified mouse tumor lines; the five-of-five observation is the citing authors’ own result, not a finding of this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredInduction of double strand breaks in DNA by ionizing radiation or genotoxic chemotherapy leads to rapid stabilization of p53 through phosphorylation of its N terminus.
“Induction of double strand breaks in DNA by ionizing radiation or genotoxic chemotherapy leads to the rapid stabilization of p53 through phosphorylation of its N terminus (Shieh et al. 1997; Siliciano et al. 1997”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Siliciano et al. 1997
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- Authors
- Siliciano, J. D., Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., & Kastan, M. B.
- Affiliations
- National Institutes of Health (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1997-12-15
- Volume
- 11
- Issue
- 24
- Pages
- 3471-3481
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316806
- OpenAlex
- W2149013144
- Cited by
- 818
- References
- 71
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 12 · 2019: 14 · 2018: 12 · 2017: 18 · 2016: 22 · 2015: 17 · 2014: 24 · 2013: 21 · 2012: 27
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Society of Hematology
- National Institutes of Health (ES05777)
- National Cancer Institute (CA71387, R01CA071387)
- National Institute of Environmental Health Sciences (R01ES005777, R37ES005777, ES05777)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- p53, DNA damage response, ionizing radiation, UV irradiation, post-translational modification, ATM kinase, lymphoblasts
- MeSH terms
- Ataxia Telangiectasia, Binding Sites, Cells, Cultured, DNA, DNA Damage, Electrophoresis, Humans, Lymphocytes, Nuclear Proteins, Peptide Fragments, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Serine, Ultraviolet Rays, Signal Transduction, Tumor Suppressor Protein p53, Cyclins, Cyclin-Dependent Kinase Inhibitor p21, Proto-Oncogene Proteins c-mdm2
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