About

William Marzluff is a Kenan Distinguished Professor of Biochemistry and Biophysics at the University of North Carolina at Chapel Hill, with a joint appointment in Biology. His research focuses on the regulation of gene activity in animal cells, particularly the regulation of gene expression during the cell cycle by posttranscriptional mechanisms. He studies systems such as the regulation of histone mRNA during the mammalian cell cycle and early development in frogs and sea urchins. His work involves understanding how histone mRNAs, which end in a conserved stem-loop structure and lack poly(A)+ tails, are processed, transported, and regulated in terms of stability and translation. Marzluff has cloned the cDNA for the stem-loop binding protein (SLBP), a critical factor in histone mRNA metabolism, and investigates how SLBP functions in RNA binding, processing, transport, and regulation of mRNA half-life, as well as how SLBP itself is regulated in connection with cell cycle regulators. His research extends to studying embryonic stages where histone mRNAs are stable across multiple cell cycles, involving cloned embryo-specific SLBPs from frogs and sea urchins, and examining the roles of G1 cyclins, cyclin D and E, in early cell cycle regulation.

Research topics

• Biology
• Genetics
• Cell biology
• Molecular biology
• Virology
• Medicine
• Computational biology

Selected publications

• DDX3X-mediated translation of structured cardiac mRNAs is essential for female heart development

  Genes & Development · 2026-04-27

  preprintOpen access

  Sex differences influence congenital heart disease (CHD) development, yet underlying molecular mechanisms remain largely unclear. We demonstrate that the X-linked RNA helicase DDX3X associates in the heart with ribosomal subunit proteins, and eCLIP mapping reveals its preferential binding to cardiac mRNAs with long, structured 5′ untranslated regions (UTRs) that can hinder translation. Using a cardiomyocyte-specific mouse Ddx3x knockout model, we show that female embryos lacking Ddx3x die at midgestation from heart failure due to impaired translation of key cardiac regulators, whereas male littermates survive. Ribosome profiling and proteomics demonstrate that DDX3X is required for efficient translation of female differential cardiac mRNAs. Reporter assays confirm that translation of essential cardiac genes such as Srf and Rcor2 depends on their 5′ UTRs and requires DDX3X. These findings uncover a sex-specific posttranscriptional mechanism by which DDX3X safeguards female heart development through selective mRNA translation, providing insight into how X-linked dosage-sensitive regulators contribute to CHD.

  PublisherDOI

• Molecular mechanisms of recruitment, function and regulation of UPF1 in histone mRNA decay

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-24 · 1 citations

  preprintOpen access

  Abstract Animal replication-dependent histone mRNAs end in a conserved stem loop (SL) instead of the canonical poly(A) tail present in all other eukaryotic mRNAs. Degradation of the histone SL at the end of the S-phase is initiated by the stem-loop binding protein SLBP and its interplay with the RNA helicase UPF1 and the exoribonuclease 3’hExo. We report direct interactions between SLBP and UPF1 and show that the unstructured SLBP N-terminus wraps around the UPF1 helicase core, contacting it at multiple sites. Although binding of SLBP to UPF1 impedes unwinding activity, it is critical for efficient histone mRNA decay in cells, as unwinding of the SL facilitates degradation by 3’hExo. Here we show that the UPF1-activator, UPF2, binds 3’hExo, and that UPF2-mediated activation of UPF1 overrides the inhibitory effect of SLBP. Our results highlight the intricate network of UPF1-centric protein-protein and protein/RNA interactions that fine-tunes its unwinding activity and orchestrates timely and efficient degradation of histone mRNA.

  PublisherOA PDFDOI

• Composition and RNA binding specificity of metazoan RNase MRP

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-23

  preprintOpen access

  Abstract Ribonuclease (RNase) MRP is a conserved RNA-based enzyme that is essential for maturation of ribosomal RNA (rRNA) in eukaryotes. However, the composition and RNA substrate specificity of this multisubunit ribonucleoprotein complex in higher eukaryotes remain a mystery. Here, we identify NEPRO and C18ORF21 as constitutive subunits of metazoan RNase MRP. Both proteins are specific to RNase MRP and are the only ones distinguishing this enzyme from the closely related RNase P, which selectively cleaves transfer RNA-like substrates. We find that NEPRO and C18ORF21 each form a complex with all other subunits of RNase MRP, stabilize its catalytic RNA, and are required for rRNA maturation and cell proliferation. We harness our discovery to identify a full suite of in vivo RNA targets of each enzyme, including positions of potential cleavage sites at nucleotide resolution. These findings resolve the general composition of metazoan RNase MRP, illuminate its RNA binding specificity, and provide valuable assets for functional exploration of this essential eukaryotic enzyme.

  PublisherOA PDFDOI

• Reversible proliferative arrest induced by rapid depletion of RNase MRP

  Nature Communications · 2025-06-18 · 3 citations

  articleOpen access

  Cellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthesis, induces a long-term yet reversible proliferative arrest in human cells. Severely compromised biogenesis of rRNAs along with acute transcriptional reprogramming precede a gradual decline of the critical cellular functions. Unexpectedly, many arresting cells show increased levels of histone mRNAs, which accumulate locally in the cytoplasm, and S-phase DNA amount. The ensuing proliferative arrest is entered from multiple stages of the cell cycle and can last for several weeks with uncompromised cell viability. Strikingly, restoring expression of RNase MRP leads to a complete reversal of the arrested state with resumed cell proliferation at the speed of control cells. We suggest that targeting rRNA biogenesis may provide a general strategy for rapid induction of a reversible proliferative arrest, with implications for understanding and manipulating cellular quiescence.

  PublisherOA PDFDOI

• Using NMR to Monitor TET-Dependent Methylcytosine Dioxygenase Activity and Regulation

  UNC Libraries · 2025-01-10

  articleOpen access

  The active removal of DNA methylation marks is governed by the ten-eleven translocation (TET) family of enzymes (TET1-3), which iteratively oxidize 5-methycytosine (5mC) into 5-hydroxymethycytosine (5hmC), and then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). TET proteins are frequently mutated in myeloid malignancies or inactivated in solid tumors. These methylcytosine dioxygenases are &alpha;-ketoglutarate (&alpha;KG)-dependent and are, therefore, sensitive to metabolic homeostasis. For example, TET2 is activated by vitamin C (VC) and inhibited by specific oncometabolites. However, understanding the regulation of the TET2 enzyme by different metabolites and its activity remains challenging because of limitations in the methods used to simultaneously monitor TET2 substrates, products, and cofactors during catalysis. Here, we measure TET2-dependent activity in real time using NMR. Additionally, we demonstrate that <em>in vitro</em> activity of TET2 is highly dependent on the presence of VC in our system and is potently inhibited by an intermediate metabolite of the TCA cycle, oxaloacetate (OAA). Despite these opposing effects on TET2 activity, the binding sites of VC and OAA on TET2 are shared with &alpha;KG. Overall, our work suggests that NMR can be effectively used to monitor TET2 catalysis and illustrates how TET activity is regulated by metabolic and cellular conditions at each oxidation step.

  PublisherDOI

• Lifetime of ground conformational state determines the activity of structured RNA

  Nature Chemical Biology · 2025-02-12 · 3 citations

  articleOpen access
  PublisherOA PDFDOI

• SUMO2 promotes histone pre-mRNA processing by stabilizing histone locus body interactions and facilitating U7 snRNP assembly

  Genes & Development · 2025-07-10

  articleOpen access

  Histone mRNAs are the only nonpolyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in promoting histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3' end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By overexpressing the U7 snRNP-specific components Lsm11 and U7 snRNA, we rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N terminus required for efficient formation of U7 snRNP. Collectively, we demonstrated that SUMO2 promotes histone pre-mRNA 3' end processing by stabilizing HLB interactions and facilitating U7 snRNP assembly.

  PublisherDOI

• SUMO2 Promotes Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Facilitating U7 snRNP Assembly

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-18

  preprint

  ABSTRACT Histone mRNAs are the only non-polyadenylated mRNAs in eukaryotic cells and require specialized processing in the histone locus body (HLB), a nuclear body where essential processing factors, including the U7 snRNP, are concentrated. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in promoting histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3’ end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By over-expressing U7 snRNP-specific components, Lsm11 and U7 snRNA, we rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N-terminus required for efficient formation of U7 snRNP. Collectively, we demonstrate that SUMO2 promotes histone pre-mRNA 3’ end processing by stabilizing HLB interactions and facilitating U7 snRNP assembly.

  PublisherDOI

• Composition and RNA binding specificity of metazoan RNase MRP

  Nucleic Acids Research · 2025-08-08 · 5 citations

  articleOpen access

  Ribonuclease (RNase) MRP is a conserved RNA-based enzyme best known for its essential role in the maturation of ribosomal RNA (rRNA) in eukaryotes. However, the composition and RNA substrate specificity of this multisubunit ribonucleoprotein complex in higher eukaryotes remain a mystery. Here, we identify NEPRO and C18ORF21 (which we renamed RMP64 and RMP24, respectively) as constitutive subunits of metazoan RNase MRP. These proteins are unique to RNase MRP and absent from the closely related RNase P, which processes transfer RNA (tRNA) precursors and tRNA-like substrates. We find that RMP64 and RMP24 are integral subunits of RNase MRP, stabilize its catalytic RNA, and are required for rRNA maturation and cell proliferation. Leveraging these discoveries, we identify a broad suite of in vivo RNA-binding targets of each enzyme, including potential cleavage sites at nucleotide resolution. Our findings identify the first metazoan RNase MRP-specific protein subunits and define the RNA-targeting repertoire of this essential enzyme in mammalian cells.

  PublisherOA PDFDOI

• Cell-cycle–regulated transcriptional pausing of <i>Drosophila</i> replication-dependent histone genes

  Molecular Biology of the Cell · 2025-05-21 · 4 citations

  article

  Coordinated expression of replication-dependent (RD) histones genes occurs within the Histone Locus Body (HLB) during S-phase, but the molecular steps in transcription that are cell-cycle regulated are unknown. We report that Drosophila RNA Pol II promotes HLB formation and is enriched in the HLB outside of S-phase, including G 1 -arrested cells that do not transcribe RD histone genes. In contrast, the transcription elongation factor Spt6 is enriched in HLBs only during S-phase. Proliferating cells in the wing and eye primordium express full-length histone mRNAs during S-phase but express only short nascent transcripts in cells in G 1 or G 2 consistent with these transcripts being paused and then terminated. Full-length transcripts are produced when Cyclin E/Cdk2 is activated as cells enter S-phase. Thus, activation of transcription elongation by Cyclin E/Cdk2 and not recruitment of RNA pol II to the HLB is the critical step that links histone gene expression to cell-cycle progression.

  PublisherDOI

Recent grants

• NIH Grant T32GM008581

  NIH · $1.6M · 2009

• NIH Grant R01GM027789

  NIH · $1.9M · 1999

• Control of Histone mRNA Levels

  NIH · $11.6M · 1982–2024

• NIH Grant R01GM076660

  NIH · $1.1M · 2010

• Histone mRNA Regulation in Development

  NIH · $11.9M · 2024–2025

Frequent coauthors

• Robert J. Duronio

  104 shared

• Zbigniew Domiński

  University of North Carolina at Chapel Hill

  72 shared

• Gary M. Wessel

  Brown University

  62 shared

• Richard O. Hynes

  Howard Hughes Medical Institute

  48 shared

• Odile Mulner‐Lorillon

  Centre National de la Recherche Scientifique

  45 shared

• Julia Morales

  Baylor College of Medicine

  45 shared

• Antonio Fernández-Guerra

  University of Copenhagen

  45 shared

• Bertrand Cosson

  Centre National de la Recherche Scientifique

  45 shared

Labs

• William Marzluff LabPI

Education

• Ph.D., Biochemistry

  University of California, San Francisco

  1980

• M.S., Biochemistry

  University of California, San Francisco

  1976

• B.S., Chemistry

  University of California, San Diego

  1974

Awards & honors

• UNC School of Medicine Executive Associate Dean for Research…
• Kenan Distinguished Professorship, 2002