ATF3 and p15PAF are novel gatekeepers of genomic integrity upon UV stress.
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.
Turchi
L
L
INSERM U898, Nice F-06107, France.
Fareh
M
M
Aberdam
E
E
Kitajima
S
S
Simpson
F
F
Wicking
C
C
Aberdam
D
D
Virolle
T
T
D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D016678:Genome; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism / Q000494:pharmacology; D014466:Ultraviolet Rays
D051700:Activating Transcription Factor 3; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C425208:PCLAF protein, human; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering