Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous largescale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.Cancer forms and progresses through a series of critical transitions-from pre-malignant to malignant states, from locally contained to metastatic disease, and from treatment-responsive to treatment-resistant tumors (Figure 1). Although specifics differ across tumor types and patients, all transitions involve complex dynamic interactions between diverse pre-malignant, malignant, and non-malignant cells (e.g., stroma cells and immune cells), often organized in specific patterns within the tumor
H/ACA RNA-protein complexes, comprised of four proteins and an H/ACA guide RNA, modify ribosomal and small nuclear RNAs. The H/ACA proteins are also essential components of telomerase in mammals. Cbf5 is the H/ACA protein that catalyzes isomerization of uridine to pseudouridine in target RNAs. Mutations in human Cbf5 (dyskerin) lead to dyskeratosis congenita. Here, we describe the 2.1 A crystal structure of a specific complex of three archaeal H/ACA proteins, Cbf5, Nop10, and Gar1. Cbf5 displays structural properties that are unique among known pseudouridine synthases and are consistent with its distinct function in RNA-guided pseudouridylation. We also describe the previously unknown structures of both Nop10 and Gar1 and the structural basis for their essential roles in pseudouridylation. By using information from related structures, we have modeled the entire ribonucleoprotein complex including both guide and substrate RNAs. We have also identified a dyskeratosis congenita mutation cluster site within a modeled dyskerin structure.
Nop56p and Nop58p are two core proteins of the box C/D snoRNPs that interact concurrently with fibrillarin and snoRNAs to function in enzyme assembly and catalysis. Here we report the 2.9 A resolution co-crystal structure of an archaeal homolog of Nop56p/Nop58p, Nop5p, in complex with fibrillarin from Archaeoglobus fulgidus (AF) and the methyl donor S-adenosyl-L-methionine. The N-terminal domain of Nop5p forms a complementary surface to fibrillarin that serves to anchor the catalytic subunit and to stabilize cofactor binding. A coiled coil in Nop5p mediates dimerization of two fibrillarin-Nop5p heterodimers for optimal interactions with bipartite box C/D RNAs. Structural analysis and complementary biochemical data demonstrate that the conserved C-terminal domain of Nop5p harbors RNA-binding sites. A model of box C/D snoRNP assembly is proposed based on the presented structural and biochemical data.
Proper protein localization is essential for all cells. However, the precise mechanism by which high fidelity is achieved is not well understood for any targeting pathway. To address this fundamental question we investigated the signal recognition particle (SRP) pathway in E. coli, which delivers proteins to the bacterial inner membrane through recognition of signal sequences on cargo proteins. Fidelity was thought to arise from the inability of SRP to bind strongly to incorrect cargos. Using biophysical assays, we found that incorrect cargos were also rejected through a series of checkpoints during subsequent steps of targeting. Thus high fidelity is achieved through the cumulative effect of multiple checkpoints; this principle may be generally applicable to other pathways involving selective signal recognition.
Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDAapproved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research.
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