Brenda Bass
· ProfessorVerifiedUniversity of Utah · Biology
Active 1978–2026
About
Brenda Bass is a Distinguished Professor of Biochemistry and an Adjunct Professor of Human Genetics at the University of Utah. Her research focuses on double-stranded RNA (dsRNA), its biological functions, and the proteins that bind to it to mediate these functions. She investigates how cells distinguish between cellular dsRNA (self) and viral dsRNA (non-self), performing genome-wide analyses to map long dsRNA expressed in organisms such as C. elegans, mouse, and human. Her work explores the recognition of viral dsRNA by RIG-I-like receptors (RLRs) in vertebrates and the role of Dicer in invertebrates, revealing evolutionary differences in innate immune pathways. Bass's research aims to understand the mechanisms of antiviral defense, the evolution of innate immune pathways, and the biological functions of dsRNA binding proteins like ADARs and Dicer. Her contributions include using structural biology and biochemistry to elucidate the mechanisms of these proteins and their roles in immune responses.
Research topics
- Genetics
- Biology
- Cell biology
- Biochemistry
- Molecular biology
- Computational biology
Selected publications
Molecular Biology of the Cell · 2026-02-18
articleOpen accessSenior authorOrsay virus (OV) is a positive-sense, single-stranded RNA (+ssRNA) virus that naturally infects Caenorhabditis elegans intestines. Like other +ssRNA viruses, the OV-encoded RNA-dependent RNA polymerase (oRdRP) synthesizes complementary antigenome for use as template for amplifying viral genome, but OV replication intermediates are underexplored. Using PCR, we observed viral genome in vast excess of antigenome, as for other +ssRNA viruses. Unlike interferon-based antiviral defense, C. elegans utilizes RNA interference (RNAi) for antiviral defense, producing sense and antisense small interfering RNAs (siRNAs) that cannot be distinguished from genome and antigenome with conventional hybridization protocols. Fluorescence-based imaging in C. elegans intestines using probes to antigenomic sequences revealed cytoplasmic as well as perinuclear localization patterns. The latter depended on factors required for generation of primary, but not secondary, siRNAs, connecting the antigenomic hybridization pattern to RNAi. We also observed cytoplasmic double-stranded RNA (dsRNA) associated with oRdRP, suggesting viral replication hubs, as well as infection-induced nuclear dsRNA, likely from endogenous dsRNA. Finally, using antibodies to oRdRP, we observed spherical structures of ∼1µm in diameter with oRdRP at their surface, which decrease in animals lacking RDE-1. Our study defines features of OV replication intermediates, setting the stage for understanding their connection to host antiviral pathways.
SSRN Electronic Journal · 2025-01-01
preprintOpen accessSenior authorbioRxiv (Cold Spring Harbor Laboratory) · 2025-02-16 · 1 citations
preprintOpen accessSenior authorCorrespondingAbstract A fully functional Dicer helicase, present in the modern arthropod, uses energy generated during ATP hydrolysis to power translocation on bound dsRNA, enabling the processive dsRNA cleavage required for efficient antiviral defense. However, modern Dicer orthologs exhibit divergent helicase functions that affect their ability to contribute to antiviral defense, and moreover, mechanisms that couple ATP hydrolysis to Dicer helicase movement on dsRNA remain enigmatic. Here, we used biochemical and structural analyses of ancestrally reconstructed Dicer helicases to map evolution of dsRNA binding affinity, ATP hydrolysis and translocation. We found that loss of affinity for dsRNA occurred early in Dicer evolution, coinciding with a decline in translocation activity, despite preservation of ATP hydrolysis activity, exemplified by the ancient deuterostome Dicer. Ancestral nematode Dicer also exhibited significant decline in ATP hydrolysis and translocation, but studies of antiviral activities in the modern nematode C. elegans indicate Dicer retained a role in antiviral defense by recruiting a second helicase. Cryo-EM analyses of an ancient metazoan Dicer allowed capture of multiple helicase states revealing the mechanism that connects each step of ATP hydrolysis to unidirectional movement along dsRNA. Overall, our study rationalizes the diversity in modern Dicer helicases by connecting ancestral functions to observations in extant enzymes. Significance Statement Among invertebrates, the contribution of Dicer’s helicase to recognition and elimination of viral double-stranded RNA varies from phylum to phylum. At the extreme end of the spectrum, vertebrate Dicers show no helicase activity. On the other end, an arthropod ortholog uses helicase translocation to efficiently move double-stranded RNA into Dicer’s cleavage site. The biochemical and structural basis of Dicer’s helicase function, as well as the evolutionary events that contribute to a divergence in function, have remained unknown. This study shows how ancient Dicer helicase tightly binds double-stranded RNA and couples ATP hydrolysis to movement along this substrate. In addition, the data reveal how components of this intricate system declined along different clades of animal evolution.
The importance of IP6 for ADAR RNA-editing enzymes and antiviral defense
Proceedings of the National Academy of Sciences · 2025-01-21
letterOpen access1st authorCorrespondingAdenosine Deaminases that act on RNA (ADARs) are RNAediting enzymes that convert Adenosine (A) to Inosine (I) in double-stranded RNA (dsRNA).ADARs are widely studied for their roles in editing endogenous dsRNA to preclude its recognition as viral dsRNA and an aberrant immune response, which can be devastating for human health ( 1 ).This important function is conserved, and organisms as evolutionary distant as human and the nematode Caenorhabditis elegans use ADARs to preclude an immune response ( 2 ).About 20 y ago, the first structure of an ADAR was solved ( 3 ), serendipitously revealing a previously unrecognized cofactor, inositol hexakisphosphate (IP6).The ADAR field was excited, envisioning interesting regulatory mechanisms that might link inositol pathways to ADARs.However, as the literature tallied up more examples of IP6 in seemingly unrelated proteins, the putative regulatory pathways were replaced by the idea that for unknown and perhaps unimportant reasons, IP6 had simply been co-opted to help proteins fold into their three-dimensional shapes.Genetic screens are notorious for uncovering pathways and relationships, and in PNAS, Xu et al. describe a screen in C. elegans that once again reveals a connection between IP6, ADARs, and dsRNA ( 4 ).While some findings were expected from prior studies, the report is important because it reminds us that this story is not over and, notably, provides connections that set the stage for continued studies to understand the role of IP6 in ADARs.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-18
preprintOpen accessSenior authorCorrespondingAbstract In C. elegans , antiviral RNA interference (RNAi) relies on the coordinated activity of Dicer (DCR-1), the helicase DRH-1, and the double-stranded RNA (dsRNA)-binding protein, RDE-4, yet the domain-specific contributions of RDE-4 remain unclear. Here, we reconstituted the antiviral complex from independently purified DCR-1•DRH-1 and RDE-4 to define how RDE-4 stabilizes and activates the complex. Addition of recombinant RDE-4 restored ATP hydrolysis and dsRNA cleavage to levels previously observed with the pre-assembled complex, and time-course assays revealed that RDE-4 is essential for maintaining DCR-1•DRH-1 activity. Mutational analysis of RDE-4 revealed that both dsRBM2 and dsRBM3, but not dsRBM1, are required for reconstituting ATP hydrolysis and cleavage. Disruption of the KKxAK motif in dsRBM2 drastically reduced dsRNA affinity and abolished catalytic rescue despite preserving robust binding to DCR-1•DRH-1. Mass photometry and pulldown assays revealed that RDE-4 primarily forms DCR-1 containing complexes, predominantly through interaction with dsRBM3, with no evidence for stable interaction with DRH-1 alone. Functionally, RDE-4 enhanced DRH-1-driven ATP hydrolysis on both 52 and 106 base-pair dsRNAs, but cleavage efficiency showed strong length dependence, implicating dsRNA substrate length as an effector in this system. Our findings establish RDE-4 as an important stabilizer of the antiviral complex and reveal distinct roles for dsRBM2 and dsRBM3 in ATP hydrolysis and dsRNA cleavage. Furthermore, our results suggest that substrate length modulates RDE-4 function, not just alone, but within the antiviral complex. These insights refine our understanding of antiviral RNAi in C. elegans and uncover regulatory mechanisms within the antiviral complex.
Proceedings of the National Academy of Sciences · 2025-05-28 · 2 citations
articleOpen accessSenior authorCorrespondingA fully functional Dicer helicase, present in the modern arthropod, uses energy from ATP hydrolysis to power translocation on bound dsRNA, enabling the processive dsRNA cleavage required for efficient antiviral defense. However, modern Dicer orthologs exhibit divergent helicase functions that affect their ability to contribute to antiviral defense. Moreover, mechanisms that couple ATP hydrolysis to Dicer helicase movement on dsRNA remain enigmatic. We used biochemical and structural analyses of ancestrally reconstructed Dicer helicases to map evolution of dsRNA binding affinity, ATP hydrolysis and translocation. Loss of affinity for dsRNA occurred early in Dicer evolution, coinciding with a decline in translocation activity, despite preservation of ATP hydrolysis activity. Ancestral nematode Dicer also exhibited significant decline in ATP hydrolysis and translocation, but studies of antiviral activities in the modern nematode Caenorhabditis elegans indicate Dicer retained a role in antiviral defense by recruiting a second helicase. Cryogenic electron microscopy (cryo-EM) analyses of an ancient metazoan Dicer allowed capture of multiple helicase states revealing the mechanism that connects each step of ATP hydrolysis to unidirectional movement along dsRNA. Our study rationalizes the diversity in modern Dicer helicases by connecting ancestral functions to observations in extant enzymes.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-16
preprintOpen accessSenior authorCorrespondingAbstract Orsay Virus (OV) is a positive-sense, single-stranded RNA (+ssRNA) virus that naturally infects C. elegans intestines. Like other +ssRNA viruses, the OV-encoded RNA-dependent RNA polymerase (oRdRP) synthesizes complementary antigenome for use as template for amplifying viral genome, but OV replication intermediates are underexplored. Using PCR, we observed viral genome in vast excess of antigenome, as for other +ssRNA viruses. Unlike interferon-based antiviral defense, C. elegans utilizes RNA interference (RNAi) for antiviral defense, producing sense and antisense small interfering RNAs (siRNAs) that cannot be distinguished from genome and antigenome with conventional hybridization protocols. Fluorescence-based imaging in C. elegans intestines using probes to antigenomic sequences revealed cytoplasmic as well as perinuclear localization patterns. The latter depended on factors required for generation of primary, but not secondary, siRNAs, connecting the antigenomic hybridization pattern to RNAi. We also observed cytoplasmic double-stranded RNA (dsRNA) associated with oRdRP, suggesting viral replication hubs, as well as infection-induced nuclear dsRNA, likely from endogenous dsRNA. Finally, using antibodies to oRdRP, we observed spherical structures of ∼1µm in diameter with oRdRP at their surface, which decrease in animals lacking RDE-1. Our study defines features of OV replication intermediates, setting the stage for understanding their connection to host antiviral pathways. Significance Statement Orsay virus is a +ssRNA virus that infects C. elegans intestines. We advance understanding of viral replication intermediates and address the issue that for animals that use antiviral RNA interference, hybridization of probes occurs with both genome and antigenome and small interfering RNAs. Single-molecule fluorescence in-situ hybridization using antigenomic probes revealed cytoplasmic and perinuclear puncta, only upon denaturation, with perinuclear signal dependent on primary, but not secondary, siRNA biogenesis. Viral RNA-dependent RNA polymerase lined the perimeter of spherical structures of ∼1µm diameter. This study sets the stage for understanding the relationship between viral replication dynamics and antiviral RNA interference.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-27
preprintOpen accessSenior authorThe human transcriptome contains millions of A-to-I editing sites arising from an unclear number of poorly characterized dsRNAs. Editing sites are often used to infer presence of dsRNA, but this method is limited by transcription levels, read depth, ADAR expression and cannot identify unedited dsRNA. To address these limitations, we developed dsRNAscan. Applying dsRNAscan to the human genome predicted 5 million dsRNAs. Genomic distribution of dsRNAs encompassing repetitive elements was widespread, but non-repetitive dsRNAs were sparse and enriched at chromosomal tips. dsRNAscan predicted hundreds of long, highly paired dsRNAs suspected to be immunogenic, but only one was in a 3'UTR, and thus likely to challenge cytoplasmic immune sensors. We observed several thousand editing enriched regions suspected to arise from intermolecular structures, and dozens of neuronally enriched dsRNAs conserved across vertebrates. This study offers the first comprehensive set of dsRNA annotations for the human genome, available as a resource at https://dsrna.chpc.utah.edu/.
Decoding RNA mysteries: a new era for biology and medicine
2024-01-01
articleOpen access1st authorCorresponding2024-04-03
peer-reviewOpen accessSenior authorInvertebrates use the endoribonuclease Dicer to cleave viral dsRNA during antiviral defense, while vertebrates use RIG-I-like Receptors (RLRs), which bind viral dsRNA to trigger an interferon response. While some invertebrate Dicers act alone during antiviral defense, C. elegans Dicer acts in a complex with a dsRNA binding protein called RDE-4, and an RLR ortholog called DRH-1. We used biochemical and structural techniques to provide mechanistic insight into how these proteins function together. We found RDE-4 is important for ATP-independent and ATP-dependent cleavage reactions, while helicase domains of both DCR-1 and DRH-1 contribute to ATP-dependent cleavage. DRH-1 plays the dominant role in ATP hydrolysis, and like mammalian RLRs, has an N-terminal domain that functions in autoinhibition. A cryo-EM structure indicates DRH-1 interacts with DCR-1’s helicase domain, suggesting this interaction relieves autoinhibition. Our study unravels the mechanistic basis of the collaboration between two helicases from typically distinct innate immune defense pathways.
Recent grants
Elucidating roles and mechanisms of double-stranded RNA-mediated pathways
NIH · $3.0M · 2021–2026
NIH · $1.4M · 2011
NIH · $3.0M · 2016
The Biology and Biochemistry of ADAR RNA editing enzymes
NIH · $5.1M · 1990–2021
NIH · $748k · 2012
Frequent coauthors
- 91 shared
Peter Shen
University of Utah
- 33 shared
P. Joseph Aruscavage
University of Utah
- 30 shared
Daniel P. Morse
United States Naval Academy
- 22 shared
Helen Donelick
University of Utah
- 17 shared
Debra M. Eckert
University of Utah
- 17 shared
Adedeji M. Aderounmu
University of Utah
- 15 shared
Claudia Consalvo
University of Utah
- 13 shared
P. Joe Aruscavage
University of Pennsylvania
Labs
Bass LabPI
Education
B.A.
Colorado College
Ph.D.
University of Colorado, Boulder
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