1 Transcription factor RFX 7 governs a tumor suppressor network in response to p 53 2 and stress 3 4

26 Despite its prominence, the mechanisms through which the tumor suppressor p53 27 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as 28 a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor 29 suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative 30 analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three 31 distinct cell systems reveals that RFX7 directly controls multiple established tumor 32 suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the 33 missing link for their activation in response to p53 and stress. RFX7 target gene expression 34 correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, 35 we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work 36 establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a 37 key node in the p53 transcriptional program. 38 39 Introduction 40 41 RFX7 belongs to a family of eight transcription factors that share a highly conserved 42 DNA-binding domain (DBD) through which they can bind to cis-regulatory X-box motifs (1, 2). 43 RFX5 is the closest sibling of RFX7, and while the expression of most RFX genes is restricted 44 to specific cell types, RFX1, RFX5, and RFX7 display ubiquitous expression (2, 3). Whole45 genome sequencing efforts led us and others to discover RFX7 mutations in 13 to 15 % of 46 Epstein-Barr Virus-negative Burkitt lymphoma patients (4, 5). Additionally, genome-wide 47 association studies linked RFX7 to chronic lymphocytic leukemia (6–8). RFX7 alterations have 48 also been identified in diffuse large B cell lymphoma (9), acute myeloid leukemia (10), as well 49 as in mouse models of lymphoma (9, 11) and leukemia (12). In addition to hematopoietic 50 neoplasms, RFX7 has been associated with body fat distribution (13), Alzheimer’s disease 51 (14), and autism spectrum disorder (15), suggesting that RFX7 may function in various cell 52 types and tissues. While human RFX7 is functionally uncharacterized, first insights from animal 53 . CC-BY-NC 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted March 25, 2021. ; https://doi.org/10.1101/2021.03.25.436917 doi: bioRxiv preprint