Dr. Edward Grow

Seminar Details

Host: Dr. Bo Zhou

Time: 4:00pm-5:00pm

Location: BICH Rm 108

Seminar Abstract

DNA is widely recognized as the genetic blueprint of life, yet it is also a dynamic physical molecule capable of adopting alternative conformations beyond the canonical B-form. Among these, Z-DNA is a left-handed DNA structure that forms in response to transcription-generated torsional stress, but its physiological functions have remained enigmatic for decades. Our work addresses this long-standing question by investigating how cells recognize, generate, and utilize Z-DNA during transcription. We discovered that the strongest sites of Z-DNA in vivo occur at highly active RNA polymerase III loci, including tRNA genes, 5S rRNA genes, SINEs, and other non-coding RNA elements. Unexpectedly, we identified the RNA polymerase III subunit POLR3F as a previously unrecognized Z-DNA-binding protein that shares structural similarity with the canonical Zα domain of ADAR1 and is required for Z-DNA formation at actively transcribed tRNA genes. Using inducible degron systems, epigenomic mapping, structural modeling, and biochemical assays, we demonstrate that POLR3F is a key determinant of Z-DNA formation in living cells. Building on these findings, we are developing new single-nucleotide-resolution methods to map Z-DNA, identifying additional Z-DNA-binding proteins, and testing how Z-DNA regulates RNA polymerase III transcription, neighboring RNA polymerase II genes, and antiviral innate immunity. Together, these studies support a new model in which Z-DNA is not simply a biophysical curiosity but a regulatory DNA structure that is actively interpreted by the transcriptional machinery. Defining how cells read and exploit alternative DNA conformations will provide fundamental insights into genome regulation, transcription, and disease.