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Radiation Sensitivity and Tumor Susceptibility in ATM Phospho-Mutant ATF2 Mice
Shuangwei Li1, Sergei Ezhevsky, Antimone Dewing
1Signal Transduction Program, Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA.
Abstract:
The transcription factor ATF2 was previously shown to be an ATM substrate. Upon phosphorylation by ATM, ATF2 exhibits a transcription-independent function in the DNA damage response through localization to DNA repair foci and control of cell cycle arrest. To assess the physiological significance of this phosphorylation, we generated ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2(KI)). ATF2(KI) mice are more sensitive to ionizing radiation (IR) than wild-type (ATF2 (WT)) mice: following IR, ATF2(KI) mice exhibited higher levels of apoptosis in the intestinal crypt cells and impaired hepatic steatosis. Molecular analysis identified impaired activation of the cell cycle regulatory protein p21(Cip/Waf1) in cells and tissues of IR-treated ATF2(KI) mice, which was p53 independent. Analysis of tumor development in p53(KO) crossed with ATF2(KI) mice indicated a marked decrease in amount of time required for tumor development. Further, when subjected to two-stage skin carcinogenesis process, ATF2(KI) mice developed skin tumors faster and with higher incidence, which also progressed to the more malignant carcinomas, compared with the control mice. Using 3 mouse models, we establish the importance of ATF2 phosphorylation by ATM in the acute cellular response to DNA damage and maintenance of genomic stability.
Insights
Phosphorylation of ATF2 by ATM is crucial for DNA damage response and genomic stability. ATF2 mutant mice show increased sensitivity to radiation and accelerated tumor development, highlighting ATM-mediated ATF2 phosphorylation
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The transcription factor ATF2 is a substrate for ATM kinase.
- ATM-mediated ATF2 phosphorylation has a transcription-independent role in DNA damage response, including cell cycle arrest and DNA repair foci localization.
Purpose of the Study:
- To investigate the physiological significance of ATM-mediated ATF2 phosphorylation in vivo.
- To assess the role of ATF2 phosphorylation in response to DNA damage and tumor development.
Main Methods:
- Generation of ATF2 knock-in (ATF2(KI)) mice with mutated ATM phosphoacceptor sites (S472/S480).
- Assessment of radiation sensitivity, apoptosis, hepatic steatosis, and p21(Cip/Waf1) activation in ATF2(KI) mice post-ionizing radiation (IR).
- Analysis of tumor development in p53 knockout (p53(KO)) crossed with ATF2(KI) mice and in a two-stage skin carcinogenesis model.
Main Results:
- ATF2(KI) mice exhibit increased sensitivity to IR, higher apoptosis in intestinal crypts, and impaired hepatic steatosis.
- Impaired activation of p21(Cip/Waf1) was observed in IR-treated ATF2(KI) mice, independent of p53.
- ATF2(KI) mice showed accelerated tumor development in both p53-deficient and skin carcinogenesis models, with increased progression to malignant carcinomas.
Conclusions:
- ATM-mediated phosphorylation of ATF2 is essential for the acute cellular response to DNA damage.
- This phosphorylation plays a critical role in maintaining genomic stability and preventing accelerated tumor formation.
- The study establishes the importance of ATF2 phosphorylation by ATM in DNA damage response and tumor suppression using three mouse models.
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