2026-06-02 | The R2T(P) complex orchestrates the SHQ1 driven early steps of box H/ACA snoRNP maturation
Abstract The chaperones RuvBL1 and RuvBL2 are members of the AAA+ ATPase family and participate in diverse cellular processes, including DNA repair, transcriptional regulation, and assembly of macromolecular complexes such as snoRNPs. The biogenesis of box H/ACA snoRNPs additionally requires the assembly factor SHQ1. These protein-RNA complexes are essential for ribosome biogenesis and telomerase stability and are linked to diseases such as dyskeratosis congenita and cancer. Despite detailed knowledge of mature complexes, their assembly mechanisms and how they can be modulated remain unclear. We characterize a trimeric interaction between SHQ1 and RuvBL1:RuvBL2, providing insight into early maturation of the protein-only precursor of box H/ACA snoRNPs. SHQ1 binds the flexible domain II of RuvBL1:RuvBL2, corresponding to the dodecamerization interface, suggesting disruption of this interface and promotion of hexamer formation. We further purified a complex containing RuvBL1:RuvBL2, SHQ1, and DKC1, the catalytic component of H/ACA snoRNPs and a client of SHQ1. This demonstrates that SHQ1 and DKC1 can simultaneously associate with RuvBL1:RuvBL2, potentially facilitating DKC1 release and subsequent snoRNA binding. Additionally, we identified a direct interaction between SHQ1 and RPAP3, a co-chaperone of RuvBL1:RuvBL2 (within the R2TP). Hence, RPAP3 may be responsible for recruiting SHQ1:DKC1 to hexameric RuvBL1:RuvBL2 and/or assist in the AAA+ mediated dissociation of the dimer. Since SHQ1 shares a domain with PIH1D1, an integral member of the R2TP complex, our findings suggest that early H/ACA snoRNP maturation may involve the R2T instead of the previously proposed R2TP complex.
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2026-05-01 | C29-13 Somatic Variants Rescue Bone Marrow Failure, But Not Lung Disease in Patients With Germline Variants in TINF2
Abstract Introduction Telomeres are essential for genome maintenance. Rare variants disrupting telomere maintenance genes cause a spectrum of short telomere syndromes, with idiopathic pulmonary fibrosis (IPF) as the most common phenotype. Variants in the shelterin component TIN2 typically cause severe pediatric dyskeratosis congenita (DC) and bone marrow failure. However, a subset of patients with germline TINF2 variants presents with less severe, adult-onset disease, including IPF, suggesting the presence of modifying factors. Methods We identified three patients with pathogenic germline TINF2 hotspot variants evaluated at the University of Pittsburgh Medical Center for lung transplantation. Two had a family history of DC; one had a sporadic presentation. Clinical genetic testing and deep exome sequencing was used to identify somatic variants. We validated the function of somatic variants in vitro using CRISPR/Cas9-mediated genome editing in multiple cell lines and in patient-derived induced pluripotent stem cells (iPSCs). Results All three patients had somatic variants in the DNA-binding domain of POT1 where tumor-specific variants have been previously reported. Edited cells showed no signs of DNA damage, genomic instability, or altered growth kinetics. Telomeres progressively lengthened in all edited lines. iPSCs reprogrammed from patient PBMCs, which harbored both the germline TINF2 and somatic POT1 variants, also demonstrated gradual telomere lengthening, verifying the POT1 variants are functional and sufficient for telomere elongation, even in the context of the pathogenic TINF2 variant. Conclusions Somatic POT1 variants appear to rescue hematopoietic function and cause telomere lengthening in vitro. POT1 editing is efficient and does not appear to influence genome stability. We propose that genetically modifying POT1 may be an effective therapy to rescue the bone marrow of patients with short telomeres. This abstract is funded by: NA
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