FUBP1 and FUBP2: A “Buddy System” Essential for Cell Survival

Authors

• Y Zheng
• R Bandle
• W Dubois
• HJ Chung
• E Batchelor
• D Levens

Abstract

FUBPs are a family of single strand DNA/RNA binding proteins, including FUBP1, FUBP2/KHSRP and FUBP3. FUBP1 binds to MYC promoter and is required for maximal expression of MYC by activating TFIIH helicase activity early in the transcription. FUBP1 and FUBP2 are both localized in cell nuclei, and are highly homologous; however, Fubp1 knockout mice are embryonically lethal with defects in multiple systems, especially hematopoiesis, while Fubp2 knockout mice are viable and fertile. To understand the cellular function of FUBP1 and FUBP2 as a system, we knocked down Fubp2 in Fubp1 knockout mouse embryonic fibroblasts (Fubp1 KO/Fubp2 KD MEFs) and tested. We found that knockdown of Fubp2 is lethal in Fubp1 knockout cells, but not in wild-type cells. In wild-type cells, knockdown of Fubp2 increases Fubp1 expression, which functionally compensates for the loss of Fubp2. Cell cycle analysis suggests DNA replication is defective in Fubp1 KO/Fubp2 KD MEFs. Whereas Fubp1 helps to constrain variation in Myc levels, co-loss of Fubp1 and Fubp2 leads to increased levels and exaggerated cell to cell variation of Myc expression. RNA-seq analysis shows that loss of Fubp1 and Fubp2 leads to global gene expression changes and alternative splicing changes. This suggests FUBP1 and FUBP2 are required for cell survival by regulating transcription, replication and RNA splicing. Furthermore, knockdown of FUBP2 is synthetically lethal with CRISPR-Cas9-mediated loss of FUBP1 in the human colon cancer cell line HCT116. Considering that FUBP1 is an established tumor suppressor that is often mutated in oligodendroglioma and other tumors while FUBP2 is intact, FUBP2 may be a novel therapeutic target for precision cancer medicine, as its inhibition specifically suppress survival of cancer cells with FUBP1 mutation, while being much less toxic to the non-cancer cells with intact FUBP1.

Scientific Focus Area: Molecular Biology and Biochemistry

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