Biology subjects

Jones, C. Y.

Publications and source records attributed to Jones, C. Y..

4 recordsLinked to original sources

bioRxiv2026

Overexpression of Eaf1, a subunit of the NuA4 lysine acetyl transferase complex, rescues growth defects in the budding yeast H3K36M oncohistone model via histone H4 tail acetylation

Histone proteins are critical for regulating nucleic acid transactions, including gene expression. Specific missense mutations in histone genes have been linked to oncogenesis, creating oncohistones. One of the first identified oncohistones converts K36 in histone H3 to M (H3K36M). While humans have 15 H3 genes, the Saccharomyces cerevisiae genome contains only two H3 genes. As H3 shares 90% sequence identity between budding yeast and humans, the budding yeast system provides an ideal model for study of H3K36M. We previously identified the catalytic subunit of the NuA4 lysine acetyltransferase complex as a high copy suppressor of growth defects in H3K36 mutant yeast cells. Here, we demonstrate that the NuA4 scaffold Eaf1 suppresses mutant H3K36 growth defects. We show that this suppression by Eaf1 is dependent on the Eaf1 HSA domain. To examine whether the role of NuA4 in acetylating histone H4 is required for suppression of H3K36 growth defects, we altered the four NuA4 target lysines within H4 (K5, 8, 12, and 16) to create quadruple histone mutants with all four of these lysines converted to alanine (H4-4K[->]A) or arginine (H4-4K[->]R). These H4 mutants have reduced viability and disrupted global H4 acetylation. Eaf1 cannot suppress growth defects in these H4 acetylation mutants, suggesting Eaf1-mediated suppression is dependent on acetylation of H4 N-terminal tails. We further show that inhibiting NuA4 activity in H3K36M human cells limits their oncogenic potential. Together, this work defines a mechanistic connection between H3K36 and H4 N-terminal tail acetylation in the context of a cancer-causing mutation. Article SummarySpecific mutations in histone genes have been found to cause various cancers, creating oncohistones, and the exact mechanisms by which they drive oncogenesis remain to be characterized. Budding yeast is a simple yet powerful model for studying oncohistones such as H3K36M. Subunits of the NuA4 lysine acetyltransferase complex were found to suppress growth defects in budding yeast expressing H3K36M. This suppression was dependent on the presence of the NuA4 target lysines in histone H4. Additionally, inhibiting NuA4 activity in human H3K36M cells limited their oncogenic potential. This work characterizes the mechanistic relationship between H3K36M and the NuA4 complex.

genetics↗

bioRxiv2023

Histone H3 E50K mutation confers oncogenic activity and supports an EMT phenotype

Sequencing of human patient tumors has identified recurrent missense mutations in genes encoding core histones. We report that mutations that convert histone H3 amino acid 50 from a glutamate to a lysine (H3E50K) support an oncogenic phenotype in human cells. Expression of H3E50K is sufficient to transform human cells as evidenced by a dramatic increase in cell migration and invasion, and a statistically significant increase in proliferation and clonogenicity. H3E50K also increases the invasive phenotype in the context of co-occurring BRAF mutations, which are present in patient tumors characterized by H3E50K. H3E50 lies on the globular domain surface in a region that contacts H4 within the nucleosome. We find that H3E50K perturbs proximal H3 post-translational modifications globally and dysregulates gene expression, activating the epithelial to mesenchymal transition. Functional studies using S. cerevisiae reveal that, while yeast cells that express H3E50K as the sole copy of histone H3 show sensitivity to cellular stressors, including caffeine, H3E50K cells display some genetic interactions that are distinct from the characterized H3K36M oncohistone yeast model. Taken together, these data suggest that additional histone H3 mutations have the potential to be oncogenic drivers and function through distinct mechanisms that dysregulate gene expression. SummaryO_LIRecurrent missense mutation that alter histone H3E50 were identified in patient tumors C_LIO_LIH3E50K expression dysregulates global H3 post-translational modification, gene expression and may govern a transcriptional program associated with metastatic phenotypes C_LIO_LIhht2-E50K yeast cells exhibit growth defects in the presence of DNA damaging agents C_LI

cancer biology↗

bioRxiv2023

Hyperextended telomeres promote C-circle formation in telomerase positive human cells

Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). The primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. To investigate C-circle formation in telomerase+ cells, we studied the human cen3tel cell line, in which telomeres progressively hyper-elongated post TERT-immortalization. cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect cECTRs. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. Two other long telomere, telomerase+ (LTT+) cell lines, HeLa1.3 (~23 kb telomeres) and HeLaE1 (~50 kb telomeres), had similar cECTR properties. Telomerase activity did not directly impact C-circle signal in LTT+ cells; instead, C-circle signal correlated with telomere length. LTT+ lines were less sensitive to hydroxyurea than an ALT+ cell line, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker.

cancer biology↗

bioRxiv2019

The DNA end-binding protein Ku associates with human telomeres primarily via protein-protein interactions

The Ku heterodimer (Ku70/Ku80) binds DNA ends with high affinity but without sequence specificity and, upon binding ends created by double-stranded breaks (DSBs), initiates canonical nonhomologous end-joining (c-NHEJ). Ku also localizes to functional telomeres where its c-NHEJ activity is inhibited. Interestingly, Ku has been co-opted at telomeres across species, where it performs varied telomeric functions. In humans, Ku is essential for its role in telomere maintenance, but how it associates with human telomeres is not known. Analysis of Kus telomere association in different populations of cen3tel cells, which had a wide range of average telomere lengths, supported Kus localization at human telomeres primarily via protein-protein interaction. We also found that the Ku70 and Ku80 5 helices, which are on opposing sides of the heterodimer and were previously implicated in Saccharomyces cerevisiae Kus NHEJ and telomeric functions, respectively, participated in Kus telomere association in human cells. While the Ku70 5 mutant showed increased interaction with TRF2, the Ku80 5 mutant was not impacted for TRF2 association. Interestingly, residues altered to impair Kus DNA end-binding function were also involved in TRF2 interaction and telomere association. Overall, our results suggest protein-protein interactions as the primary mode by which Ku associates with human telomeres.

molecular biology↗