The transcription factor ATF2 contributes to cell cycle and cell death decisions upon its phosphorylation by stress kinases. We recently discovered that ATM phosphorylates ATF2 on Ser490/8 following the formation of double-stranded DNA breaks (DSBs) by ionizing radiation (IR). Consequently, ATF2 is rapidly recruited to DSB-induced foci, where it co-localizes with gamma-H2AX as well as with DNA repair proteins such as Mre11, Rad50 and NBS1 (MRN). Inhibition of ATF2 expression impairs recruitment of Mre11 and NBS1 to the repair foci and attenuates the S-phase checkpoint, and results in hypersensitivity to IR. Furthermore, ATF2 is also required for the activation of ATM, and consequently of Chk1 and Chk2. Significantly, the newly identified role of ATF2 in DNA damage response does not require its transcriptional activity. These findings provide the foundation for our hypothesis that via distinct regulatory pathways (ATM vs. JNK/p38) ATF2 contributes to separate cellular functions: transcription,and DNA damage response and consequently, tumorigenesis. We will test this hypothesis by characterizing the requirements and the mechanism(s) underlying the newly identified function of ATF2 as a regulator of the DNA damage response as it pertains to normal cellular growth and tumorigenesis. Specifically we will: (1) Characterize ATF2 as a regulator of DNA damage in the context of histone modification and ATM activation. Earlier studies established ATF2 association with components of TIP60 histone acetyltransferase complex; ATF2 homologues in S. pombe are implicated in chromatin remodeling, which is now linked with the activation of ATM. We will characterize the role of ATF2 in histone acetylation and the induction of ATM in response to DSB; (2) Utilize fission yeast as a model to genetically dissect ATF2 homolog (Atf21, Pcr1) functions in DNA damage responses. Fission yeast has long provided a paradigm for cell cycle control and DNA damage responses. The stress signaling molecules, including ATF2, are conserved in this organism, and its genetic simplicity will be utilized to independently further develop our preliminary data and to act as a genetic model to test chromatin modifications in a well defined and controlled setting; (3) Determine the effect of p38/JNK on ATM phosphorylation of ATF2 (and vice versa) in relation to ATF2 activity in transcription and the DNA damage response in non-transformed and in tumor cells; (4) Assess which of ATF2 modifications and functions (transcription/damage response) is required for its regulation of the cell cycle, growth control, apoptosis, and tumorigenicity in non transformed and in melanoma cell lines; (5) Determine changes in the skin and melanoma tumor formation and in rate of mutagenesis in mice expressing transcriptional or ATM-mutant forms of ATF2. Overall, using the powerful genetics of S. Pombe, the relevant mammalian cell cultures combined with genetic mouse models our proposal will provide important new understanding of ATF2 in transcription and DNA damage response. ? ?
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