About

Yang Gao is an Assistant Professor of BioSciences and a CPRIT Scholar in Cancer Research at Rice University. Her laboratory utilizes structural biology techniques, including cryo-electron microscopy and x-ray crystallography, to investigate the molecular mechanisms of DNA replication, repair, and recombination. Her research focuses on characterizing how enzymes and motors work together during these processes and understanding how errors are generated during DNA replication and repair. The insights gained from her work aim to elucidate the origins of disease-related abnormalities in DNA and to identify potential targets for disease treatment, particularly in the context of cancer. Yang Gao holds a B.S. in Molecular Biology from the University of Science and Technology of China, obtained in 2007, and a Ph.D. in Biochemistry from Iowa State University, completed in 2013. Her research integrates biochemical and biophysical approaches to advance understanding of the molecular basis of genome stability and disease.

Research topics

• Chemistry
• Stereochemistry
• Biochemistry
• Organic chemistry
• Business
• Computational biology
• Combinatorial chemistry
• Biology

Selected publications

• Structural Basis of Mitochondrial Transcription Regulation via Interactions of PolRMT and TFAM with Upstream Promoter DNA

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-12

  articleOpen accessSenior authorCorresponding

  Mitochondrial DNA (mtDNA) transcription is essential for cellular energy production and is carried out by a streamlined transcription system in which transcription factor A (TFAM), transcription factor B2 (TFB2M), and the mitochondrial RNA polymerase (PolRMT) assemble at defined promoters to initiate transcription. Previous structural studies elucidated the core initiation mechanism but relied on truncated promoter templates that excluded upstream regulatory DNA interactions. Here, we present two conformations of mitochondrial transcription initiation complexes assembled on the heavy-strand promoter (HSP): a TFAM-bound complex with extended upstream DNA and a TFAM-free complex containing short linear DNA. The TFAM-bound structure reveals a transcription-stimulatory interface between PolRMT and the upstream promoter region (UPR) enabled by TFAM-induced promoter bending. Consistent with this structural observation, UPR truncation reduces transcription from all mtDNA promoters, an effect abolished by mutation of the PolRMT interface. In contrast, the TFAM-free structure reveals a transcription-inhibitory interaction of linear upstream DNA with the PolRMT tether helix, which would sterically clash with TFAM binding. Deletion of the tether helix increases off-target transcription, supporting an autoinhibitory role that enhances promoter specificity. Together, these findings reveal how TFAM-shaped promoter architecture and PolRMT regulatory elements coordinate mitochondrial transcription initiation and regulation.

  PublisherOA PDFDOI

• Structural basis of error-prone DNA synthesis by DNA polymerase θ

  Nature Communications · 2025-02-28 · 6 citations

  articleOpen accessSenior author

  DNA polymerase θ (Pol θ) is an A-family DNA polymerase specialized in DNA double-strand breaks repair and translesion synthesis. Distinct from its high-fidelity homologs in DNA replication, Pol θ catalyzes template-dependent DNA synthesis with an inherent propensity for error incorporation. However, the structural basis of Pol θ’s low-fidelity DNA synthesis is not clear. Here, we present cryo-electron microscopy structures detailing the polymerase domain of human Pol θ in complex with a cognate C:G base pair (bp), a mismatched T:G bp, or a mismatched T:T bp. Our structures illustrate that Pol θ snugly accommodates the mismatched nascent base pairs within its active site with the finger domain well-closed, consistent with our in-solution fluorescence measurement but in contrast to its high-fidelity homologs. In addition, structural examination and mutagenesis study show that unique residues surrounding the active site contribute to the stabilization of the mismatched nascent base pair. Furthermore, Pol θ can efficiently extend from the misincorporated T:G or T:T mismatches, yet with a preference for template or primer looping-out, resulting in insertions and deletions. Collectively, our results elucidate how an A-family polymerase is adapted for error-prone DNA synthesis. DNA polymerase θ plays a critical role in maintaining genome stability through its error-prone DNA synthesis. Here, the authors reveal unique features of DNA polymerase θ that underpin its error-prone polymerase activity by integrating structural and biochemical analysis.

  PublisherOA PDFDOI

• Biochemical Profiling and Structural Basis of ADAR1-Mediated RNA Editing

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-02 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Summary ADAR1 is a pivotal regulator in RNA-induced immune responses by catalyzing the conversion of adenosine to inosine on double-stranded RNA. Mutations on ADAR1 are associated with human autoimmune disease, and targeting ADAR1 has been proposed for cancer immunotherapy. However, the molecular mechanisms governing ADAR1-mediated RNA editing remain enigmatic. Here, we provide detailed biochemical and structural characterizations of human ADAR1. Our biochemical profiling reveals that ADAR1 editing is both sequence and RNA duplex length-dependent, but can well tolerate mismatches near the editing site. Moreover, our high-resolution structures of ADAR1-RNA complexes, coupled with mutagenesis studies, revealed the molecular basis for RNA binding, substrate selection, dimerization, and the crucial role of the RNA-binding domain 3 for ADAR1 editing. The ADAR1 structures also help explain the potential defects of disease-associated mutations, where biochemical and RNA-sequencing analysis further indicate some of the mutations preferentially impact the editing of RNAs with short duplex. Our findings illustrate the molecular mechanism of ADAR1 editing and provide clues for deciphering its role in immune regulation and drug targeting. HIGHLIGHTS Biochemical profiling of ADAR1 RNA substrate preference Atomic resolution structures of ADAR1 with two physiological RNA substrates Disease-related mutations of ADAR1 preferentially impact RNA editing with short dsRNA. RNA-binding domain 3 is essential for ADAR1 RNA capture and editing

  PublisherDOI

• Single-Molecule FRET Reveals Two T4 Phage MR Complex Exonuclease States Regulated by the Mre11 Dimer Interface

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-29

  preprintOpen access

  ABSTRACT The Mre11/Rad50 (MR) complex serves as an initial responder to double-stranded DNA breaks and is conserved across all domains of life. Rad50 possesses ATPase activity that provides energy for the nuclease activities of Mre11. To elucidate the variation in exonuclease activity across the T4 phage MR complex population, we conducted smFRET studies utilizing a dual-labeled Cy3 and Cy5 double-stranded DNA substrate. Our findings revealed that the wild-type (WT) MR complex population was predominantly divided into two distinct rates of exonuclease activity. The majority of the population (94%) exhibited rapid exonuclease activity, with an average rate exceeding 20 nucleotides per second, while the remaining fraction showed substantially slower exonuclease activity, averaging 0.50 nucleotides per second. Furthermore, we compared the activity of the WT population to a mutant complex harboring the Mre11 mutation L101D, which has previously been shown to disrupt the Mre11 dimer interface. The MR complex with the L101D mutation exhibited a much higher percentage of the population displaying slow exonuclease activity (78%), while the remaining population exhibited fast exonuclease activity at a rate similar to that of the WT population. Additional activity parameters were evaluated, such as pause times and transition amplitudes, under various enzyme concentrations, revealing further differences between the WT and L101D MR complexes. Our results provide new insights into the molecular mechanisms of MR complex exonuclease activity and suggest that the complex may adopt different conformations with distinct kinetic properties.

  PublisherOA PDFDOI

• A class of benzofuranoindoline-bearing heptacyclic fungal RiPPs with anticancer activities

  Nature Chemical Biology · 2025-06-23 · 10 citations

  article
  PublisherDOI

• Biochemical profiling and structural basis of ADAR1-mediated RNA editing

  Molecular Cell · 2025-03-17 · 10 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Abstract 2317 Mitochondrial Transcription Factor A (TFAM) is susceptible to oxidation, leading to a decrease in DNA binding affinity

  Journal of Biological Chemistry · 2025-05-01

  articleOpen accessSenior author

  Mitochondria are known as the powerhouse of the cell due to their production of energy through oxidative phosphorylation (OXPHOS). OXPHOS also produces reactive oxygen species (ROS) that can damage the unique mitochondrial genome (mtDNA) and its unique set of maintenance proteins. Improper maintenance of mtDNA can lead to DNA mutations, depletions, and deletions that cause diseases such as Alzheimer's Disease, cancer, and premature ageing. One key mtDNA maintenance protein is mitochondrial transcription factor A (TFAM), which is the most abundant double-strand DNA binding protein in mitochondria.

  PublisherOA PDFDOI

• BPS2025 - Single-molecule level analysis of ADAR1 binding and A-to-I editing on double-stranded RNA

  Biophysical Journal · 2025-02-01

  articleOpen access
  PublisherOA PDFDOI

• Re: Concerns Regarding the Validation of ZYS-1 as a <i>Bona Fide</i> ADAR1 Inhibitor

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-07 · 2 citations

  preprintOpen access

  Abstract Wang et al. in Nature Cancer report ZYS-1 as an ADAR1 inhibitor and present biochemical and cellular evidence to support ZYS-1’s direct interaction with and inhibition of ADAR1, including enzymatic assays, surface plasmon resonance (SPR), drug affinity responsive target stability (DARTS), and cellular thermal shift assays (CETSA). We raise critical methodological concerns regarding the validation of ZYS-1 as a bona fide ADAR1 inhibitor. Our primary concern relates to the misuse of an adenosine deaminase (ADA) activity assay kit for ADAR1 enzymatic activity characterization. Using established biochemical assays with direct inosine quantification, we evaluated ZYS-1’s inhibitory activity against ADAR1 using physiologically relevant RNA substrates. The compound showed no inhibitory activity at concentrations up to 1 mM. We demonstrate that the ADA assay kit used by Wang et al. does not reflect ADAR1-specific activity, and ZYS-1 is unable to inhibit ADAR1 in well-validated biochemical assays. We urge for further validation using ADAR1-specific assays to establish ZYS-1 as a genuine ADAR1 inhibitor.

  PublisherOA PDFDOI

• Increased matrix stiffness in pituitary neuroendocrine tumors invading the cavernous sinus is activated by TAFs: focus on the mechanical signatures

  Endocrine · 2024-09-06 · 2 citations

  article
  PublisherDOI

Recent grants

• Structural basis of replisome mediated DNA replication and repair

  NIH · $1.9M · 2021–2026

Frequent coauthors

• Terrence R. Burke

  112 shared

• Johannes Voigt

  Foghorn Therapeutics (United States)

  62 shared

• Dajun Yang

  Sun Yat-sen University Cancer Center

  50 shared

• Xiaobiao Zhang

  Zhongshan Hospital

  40 shared

• Wei Yang

  Wuhan University

  38 shared

• Ribo Guo

  35 shared

• James A. Kelley

  Center for Cancer Research

  32 shared

• Huanping Guo

  Harbin Veterinary Research Institute

  31 shared

Labs

• Yang Gao LabPI

Education

• Ph. D., BBMB

  Iowa State University

Awards & honors

• CPRIT Scholar in Cancer Research