LAUSR

Significance All positive-sense single-stranded RNA viruses, such as Zika virus (ZIKV), replicate in the cytoplasm of host cells, but they can regulate host gene expression in the nucleus. Here, we report that the ZIKV NS5, the viral RNA-dependent RNA polymerase (RdRp) and essential for the viral replication in the cytoplasm, can directly bind with chromatin DNA in the nuclei. In human neural progenitor cells, NS5 inhibits the transcription of numerous neural genes by binding onto their gene body and blocking PAF1C-mediated transcription elongation. The expression of ZIKV NS5 disrupts neurogenesis in developing mouse brain. Our findings reveal a role of ZIKV RdRp as a DNA binding protein to regulate host gene transcription and provide insights into abnormal neurodevelopment and ZIKV infection.