Biomedical subjects

Liang Tong

Publications and source records attributed to Liang Tong.

3 recordsLinked to original sources

PubMed2026

Are components of the histone gene expression machinery functionally repurposed in terminally differentiated cells?

The expression of metazoan replication-dependent histone genes is controlled by the nuclear protein at the ataxia-telangiectasia locus (NPAT) and U7 small nuclear ribonucleoprotein particle (snRNP). NPAT activates transcription of histone genes during S-phase, whereas U7 snRNP is a multi-subunit endonuclease that cleaves the resultant transcripts at the 3' end, yielding mature histone mRNAs. In cycling cells, NPAT and U7 snRNP with its four unique components, U7 snRNA, Lsm10, Lsm11 and FLASH, are highly enriched in histone locus bodies (HLBs), the nuclear condensates formed near histone gene loci. Here, we show that in muscle and neural cells that have ceased to replicate their chromatin and permanently exited the cell cycle, HLBs are dismantled and NPAT, FLASH and Lsm11 are detected in the cytoplasm. This observation suggests that in postmitotic cells, NPAT and U7 snRNP become repurposed for functions unrelated to generating histone mRNAs. We identified a highly conserved region in Lsm11 that engages in various protein-protein interactions and likely acts as a universal platform that controls the assembly, localization and function of Lsm11 complexes, including U7 snRNP, during cell growth and differentiation. Since the assembly of U7 snRNP requires survival motor neuron, the protein mutated in spinal muscular atrophy, our results may provide a new perspective on the pathophysiology of this neuromuscular disorder.

Histones↗

PubMed2026

Assessing Metal Ion Assignment Accuracy in Protein Data Bank Models via Elemental Spectroscopy.

Accurate representation of metal ions in macromolecular structures is critical for chemical interpretation, computational modeling, and machine-learning methods that rely on Protein Data Bank (PDB) entries. However, the elemental identity of metals modeled in crystallographic structures is often inferred indirectly and rarely validated experimentally. Here, we combine Particle Induced X-ray Emission (PIXE) and X-ray Fluorescence Spectroscopy (XRFS) to determine the elemental composition of protein samples used to generate 70 deposited metalloprotein crystal structures. By analyzing the original protein material employed for crystallization, but before the addition of crystallization buffer solutions, we assess whether the modeled metal ions in deposited structures are consistent with experimentally detectable elemental content. We find that in a majority of cases, the metals modeled in the corresponding PDB entries are inconsistent with the metals present in the protein samples before crystallization, or that additional metals are present but not represented in the structural models. Spectroscopic results were integrated with automated crystallographic validation metrics, including real-space Z-difference (RSZD) analysis and systematic rerefinement, to evaluate atomic-number mismatch at metal sites. PIXE and XRFS show strong agreement for dominant elemental signals and provide complementary, scalable approaches for identifying suspect metal assignments. This work does not address physiological or functional metalation but instead highlights a widespread data integrity issue in deposited macromolecular structures, PDB-wide. These results establish an experimentally corroborated link between elemental identity and crystallographic validation metrics, enabling the large-scale detection of chemically inconsistent annotations in structural databases used for computational modeling and machine learning.

Databases, Protein↗

PubMed2023

Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3.

A novel class of benzoxaboroles was reported to induce cancer cell death but the mechanism was unknown. Using a forward genetics platform, we discovered mutations in cleavage and polyadenylation specific factor 3 (CPSF3) that reduce benzoxaborole binding and confer resistance. CPSF3 is the endonuclease responsible for pre-mRNA 3'-end processing, which is also important for RNA polymerase II transcription termination. Benzoxaboroles inhibit this endonuclease activity of CPSF3 in vitro and also curb transcriptional termination in cells, which results in the downregulation of numerous constitutively expressed genes. Furthermore, we used X-ray crystallography to demonstrate that benzoxaboroles bind to the active site of CPSF3 in a manner distinct from the other known inhibitors of CPSF3. The benzoxaborole compound impeded the growth of cancer cell lines derived from different lineages. Our results suggest benzoxaboroles may represent a promising lead as CPSF3 inhibitors for clinical development.

Cleavage And Polyadenylation Specificity Factor↗