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Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
Published on: June 8, 2018
ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress
Abstract:
After genotoxic stress, normal cells trigger DNA repair or, if unable to repair, undergo apoptosis to eradicate the cells that bear the risk of becoming tumorigenic. Here we show that repression of the transcription factor, activating transcription factor 3 (ATF3), after ultraviolet (UV)-mediated genotoxic stress impairs the DNA repair process. We provide evidence that ATF3 directly regulates the proliferating cell nuclear antigen (PCNA)-associated factor KIAA0101/p15(PAF). We further show that the expressions of ATF3 and p15(PAF) is sufficient to trigger the DNA repair machinery, and that attenuation of their expression alters DNA repair mechanisms. We show that the expression of p15(PAF) compensates for a lack of ATF3 expression, thereby constituting a major effector of ATF3 in the DNA repair process. In addition, we provide evidence that p15(PAF) expression is required for the correct function of PCNA during DNA repair, as prevention of their interaction significantly alters DNA repair mechanisms. Finally, defective DNA repair, because of the downregulation of p15(PAF) expression, rendered the cells more sensitive to UV-induced cell death. Therefore, our results suggest ATF3 and p15(PAF) as novel gatekeepers of genomic integrity after UV exposure.
Insights
Activating transcription factor 3 (ATF3) and its target p15(PAF) are crucial for DNA repair after UV exposure. Their downregulation impairs DNA repair, increasing sensitivity to UV-induced cell death, highlighting their role in maintaining genomic integrity.
Area of Science:
- Molecular Biology
- Cellular Biology
- Genetics
Background:
- Normal cells repair DNA damage or undergo apoptosis to prevent tumorigenesis.
- Genotoxic stress, like UV radiation, poses a risk to genomic integrity.
Purpose of the Study:
- To investigate the role of activating transcription factor 3 (ATF3) in DNA repair following UV-induced genotoxic stress.
- To identify downstream targets of ATF3 involved in DNA repair mechanisms.
Main Methods:
- Investigated ATF3 repression after UV exposure.
- Analyzed the regulation of KIAA0101/p15(PAF) by ATF3.
- Assessed the impact of ATF3 and p15(PAF) expression on DNA repair machinery.
- Examined the interaction between p15(PAF) and proliferating cell nuclear antigen (PCNA).
Main Results:
- ATF3 repression impairs DNA repair after UV stress.
- ATF3 directly regulates p15(PAF) expression.
- ATF3 and p15(PAF) expression are sufficient to activate DNA repair.
- p15(PAF) compensates for ATF3 loss and is essential for PCNA function in DNA repair.
- Downregulation of p15(PAF) leads to defective DNA repair and increased UV sensitivity.
Conclusions:
- ATF3 and p15(PAF) act as novel gatekeepers of genomic integrity after UV exposure.
- The ATF3-p15(PAF) pathway is critical for effective DNA repair and cell survival post-UV.
- p15(PAF) plays a vital role in PCNA-mediated DNA repair processes.
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