AATF/Che-1-An RNA Binding Protein at the Nexus of DNA Damage Response and Ribosome Biogenesis.

Rainer W J Kaiser,Roman-Ulrich Müller,Francesca Fabretti,Katja Höpker,Johanna Erber

doi:10.3389/fonc.2020.00919

Abstract

The DNA damage response (DDR) is a complex signaling network that is activated upon genotoxic stress. It determines cellular fate by either activating cell cycle arrest or initiating apoptosis and thereby ensures genomic stability. The Apoptosis Antagonizing Transcription Factor (AATF/Che-1), an RNA polymerase II-interacting transcription factor and known downstream target of major DDR kinases, affects DDR signaling by inhibiting p53-mediated transcription of pro-apoptotic genes and promoting cell cycle arrest through various pathways instead. Specifically, AATF was shown to inhibit p53 expression at the transcriptional level and repress its pro-apoptotic activity by direct binding to p53 protein and transactivation of anti-apoptotic genes. Solid and hematological tumors of various organs exploit this function by overexpressing AATF. Both copy number gains and high expression levels of AATF were associated with worse prognosis or relapse of malignant tumors. Recently, a number of studies have enabled insights into the molecular mechanisms by which AATF affects both DDR and proliferation. AATF was found to directly localize to sites of DNA damage upon laser ablation and interact with DNA repair proteins. In addition, depletion of AATF resulted in increased DNA damage and decrease of both proliferative activity and genotoxic tolerance. Interestingly, considering the role of ribosomal stress in the regulation of p53, more recent work established AATF as ribosomal RNA binding protein and enabled insights into its role as an important factor for rRNA processing and ribosome biogenesis. This Mini Review summarizes recent findings on AATF and its important role in the DDR, malignancy, and ribosome biogenesis.

Highlights

Reviewed by: Vincenzo Coppola, The Ohio State University, United States Sonia Lain, Karolinska Institutet (KI), Sweden
The Apoptosis Antagonizing Transcription Factor (AATF/Che-1), an RNA polymerase II-interacting transcription factor and known downstream target of major DNA damage response (DDR) kinases, affects DDR signaling by inhibiting p53-mediated transcription of pro-apoptotic genes and promoting cell cycle arrest through various pathways instead
The molecular machinery essential for protein synthesis [24, 25], being key players at the nexus of anabolism and cell growth, these findings suggested a possible function of AATF/Traube in ribosomal biogenesis for the first time

Summary

NOVEL ASPECTS OF THE INTERPLAY OF AATF AND THE DDR

Another study from our group described new findings regarding the interaction between AATF and the DDR. These complexes, consisting of ribosomal and nucleolar proteins as well as several RNA biotypes including snoRNA, are essential for both rRNA transcription and processing, crucially affecting ribosome assembly [44, 45] These data are in line with evidence recently published by Pineiro et al [46], who identified the RNA-polymerase I (RNAPI)-transcribed RNA-protein interactome and established AATF as an RNAPI-associated RBP itself. Since rRNA transcription and ribosome biogenesis are required for cell growth and division, AATF-driven increase in ribosome density may contribute to the proliferative potential of malignant tumors In line with this hypothesis, elevated ribosome synthesis has been shown to be a risk factor of malignancy [26], prompting the development of antineoplastic therapies that target the ribosome [55]. Whichever the therapeutic molecule of choice—broadening our knowledge of the spatiotemporal functions and characteristics of AATF in both healthy and pathological states will be pivotal to advancing therapeutic options (Figures 2A,B)

CONCLUSION

AUTHOR CONTRIBUTIONS