Browsing by Author "Bates, Alison M."

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    Hachimoji DNA and RNA: A genetic system with eight building blocks
    (American Association for the Advancement of Science, 2019-02-22) Hoshika, Shuichi; Leal, Nicole A.; Kim, Myong-Jung; Kim, Myong-Sang; Karalkar, Nilesh B.; Kim, Hyo-Joong; Bates, Alison M.; Watkins, Norman E., Jr.; SantaLucia, Holly A.; Meyer, Adam J.; DasGupta, Saurja; Piccirilli, Joseph A.; Ellington, Andrew D.; SantaLucia, John, Jr.; Georgiadis, Millie M.; Benner, Steven A.; Biochemistry and Molecular Biology, School of Medicine
    Reported here are DNA and RNA-like systems built from eight (hachi-) nucleotide letters (-moji) that form four orthogonal pairs. This synthetic genetic biopolymer meets the structural requirements needed to support Darwinism, including a polyelectrolyte backbone, predictable thermodynamic stability, and stereoregular building blocks that fit a Schrödinger aperiodic crystal. Measured thermodynamic parameters predict the stability of hachimoji duplexes, allowing hachimoji DNA to double the information density of natural terran DNA. Three crystal structures show that the synthetic building blocks do not perturb the aperiodic crystal seen in the DNA double helix. Hachimoji DNA was then transcribed to give hachimoji RNA in the form of a functioning fluorescent hachimoji aptamer. These results expand the scope of molecular structures that might support life, including life throughout the cosmos.
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    Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma
    (MDPI, 2019-05-04) Huda, Nazmul; Xu, Yan; Bates, Alison M.; Rankin, Deborah A.; Kannan, Nagarajan; Gilley, David; Pathology and Laboratory Medicine, School of Medicine
    Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.
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    Structural and genome-wide analyses suggest that transposon-derived protein SETMAR alters transcription and splicing
    (Elsevier, 2022) Chen, Qiujia; Bates, Alison M.; Hanquier, Jocelyne N.; Simpson, Edward; Rusch, Douglas B.; Podicheti, Ram; Liu, Yunlong; Wek, Ronald C.; Cornett, Evan M.; Georgiadis, Millie M.; Biochemistry and Molecular Biology, School of Medicine
    Extensive portions of the human genome have unknown function, including those derived from transposable elements. One such element, the DNA transposon Hsmar1, entered the primate lineage approximately 50 million years ago leaving behind terminal inverted repeat (TIR) sequences and a single intact copy of the Hsmar1 transposase, which retains its ancestral TIR-DNA-binding activity, and is fused with a lysine methyltransferase SET domain to constitute the chimeric SETMAR gene. Here, we provide a structural basis for recognition of TIRs by SETMAR and investigate the function of SETMAR through genome-wide approaches. As elucidated in our 2.37 Å crystal structure, SETMAR forms a dimeric complex with each DNA-binding domain bound specifically to TIR-DNA through the formation of 32 hydrogen bonds. We found that SETMAR recognizes primarily TIR sequences (∼5000 sites) within the human genome as assessed by chromatin immunoprecipitation sequencing analysis. In two SETMAR KO cell lines, we identified 163 shared differentially expressed genes and 233 shared alternative splicing events. Among these genes are several pre-mRNA-splicing factors, transcription factors, and genes associated with neuronal function, and one alternatively spliced primate-specific gene, TMEM14B, which has been identified as a marker for neocortex expansion associated with brain evolution. Taken together, our results suggest a model in which SETMAR impacts differential expression and alternative splicing of genes associated with transcription and neuronal function, potentially through both its TIR-specific DNA-binding and lysine methyltransferase activities, consistent with a role for SETMAR in simian primate development.