fig1

Figure 1. Model of NANOG regulation by DR2 Alu and the effect of POLR3G depletion. NANOG-Alu-Sx is a member of the DR2 family of Alu SINEs that lies approximately 6 kb upstream of the NANOG gene. A positive feedback loop exists between the expression of NANOG and the POLR3G subunit of pol III. Undifferentiated prostate cancer cells express NANOG, which binds the promoter of the POLR3G gene and stimulates its transcription by pol II. The POLR3G protein is incorporated into pol III, which binds to DR2 Alu SINEs, such as NANOG-Alu-Sx, but supports relatively inefficient transcription. POLR3G depletion by small molecule ML-60218 or RNAi allows replacement of pol III by pol II at DR2 Alu and increases transcription of these SINEs. DR2 Alu RNA is processed by DICER to generate small (~105 nts) repeat-induced RNAs (riRNA) with complementary sequence to the NANOG mRNA; this results in AGO-mediated degradation of NANOG mRNA, inhibiting self-renewal and allowing differentiation.