Biology subjects

Komar, A. A.

Publications and source records attributed to Komar, A. A..

3 recordsLinked to original sources

bioRxiv2026

METTL16 promotes taxane resistance in Triple-Negative Breast Cancer through m6A-dependent translational upregulation of ABCB1

Triple-negative breast cancer (TNBC) commonly develops resistance to taxane-based chemotherapy, resulting in recurrence and poor clinical outcomes. Defining the molecular mechanisms that sustain chemoresistance is essential for improving therapeutic efficacy. Using unbiased insertional mutagenesis, we identified the RNA methyltransferase METTL16 as a previously unrecognized epi-transcriptomic driver of taxane resistance. METTL16 overexpression conferred resistance to docetaxel and paclitaxel across multiple TNBC models, and METTL16 expression was elevated in paclitaxel-resistant cells. Genetic depletion of METTL16 in paclitaxel-resistant cells restored taxane sensitivity. Because enhanced drug efflux is a well-established mechanism of taxane resistance, we investigated whether METTL16 regulates the multidrug transporter ABCB1 (P-glycoprotein). Paclitaxel-resistant TNBC cells exhibited elevated METTL16 and ABCB1 expression compared to parental cells. METTL16 binds to ABCB1 mRNA and catalyzes its N6-methyladenosine (m6A) modification, promoting increased ribosome loading and translational upregulation without altering transcript abundance. Inactivation of METTL16 impaired ABCB1 polysome association and restored paclitaxel sensitivity, demonstrating that the methyltransferase activity is essential for resistance. Consistent with this mechanism, METTL16 overexpression increased ABCB1 protein levels, whereas METTL16 down-regulation increased intracellular paclitaxel accumulation. Analysis of TNBC patient datasets revealed a positive correlation between METTL16 and ABCB1 expression, supporting the clinical relevance of this mechanism. Antisense-mediated inhibition of METTL16 using a translation-blocking Vivo-Morpholino reduced the survival of resistant TNBC cells and suppressed tumor growth in vivo. Surprisingly, genetic ablation of METTL16 caused profound loss of TNBC cell viability, while having only modest effects on nonmalignant mammary epithelial cells, indicating a cancer-selective dependency. Collectively, these findings define a METTL16-ABCB1 interaction that drives taxane resistance and establish METTL16 as a therapeutic target in TNBC.

cancer biology↗

bioRxiv2020

Potential impact on coagulopathy of gene variants of coagulation related proteins that interact with SARS-CoV-2

Thrombosis has been one of the complications of the Coronavirus disease of 2019 (COVID-19), often associated with poor prognosis. There is a well-recognized link between coagulation and inflammation, however, the extent of thrombotic events associated with COVID-19 warrants further investigation. Poly(A) Binding Protein Cytoplasmic 4 (PABPC4), Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1) and Vitamin K epOxide Reductase Complex subunit 1 (VKORC1), which are all proteins linked to coagulation, have been shown to interact with SARS proteins. We computationally examined the interaction of these with SARS-CoV-2 proteins and, in the case of VKORC1, we describe its binding to ORF7a in detail. We examined the occurrence of variants of each of these proteins across populations and interrogated their potential contribution to COVID-19 severity. Potential mechanisms by which some of these variants may contribute to disease are proposed. Some of these variants are prevalent in minority groups that are disproportionally affected by severe COVID-19. Therefore, we are proposing that further investigation around these variants may lead to better understanding of disease pathogenesis in minority groups and more informed therapeutic approaches. Author summaryIncreased blood clotting, especially in the lungs, is a common complication of COVID-19. Infectious diseases cause inflammation which in turn can contribute to increased blood clotting. However, the extent of clot formation that is seen in the lungs of COVID-19 patients suggests that there may be a more direct link. We identified three human proteins that are involved indirectly in the blood clotting cascade and have been shown to interact with proteins of SARS virus, which is closely related to the novel coronavirus. We examined computationally the interaction of these human proteins with the viral proteins. We looked for genetic variants of these proteins and examined how these variants are distributed across populations. We investigated whether variants of these genes could impact severity of COVID-19. Further investigation around these variants may provide clues for the pathogenesis of COVID-19 particularly in minority groups.

bioinformatics↗

bioRxiv2020

Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design

As the SARS-CoV-2 pandemic is rapidly progressing, the need for the development of an effective vaccine is critical. A promising approach for vaccine development is to generate, through codon pair deoptimization, an attenuated virus. This approach carries the advantage that it only requires limited knowledge specific to the virus in question, other than its genome sequence. Therefore, it is well suited for emerging viruses for which we may not have extensive data. We performed comprehensive in silico analyses of several features of SARS-CoV-2 genomic sequence (e.g., codon usage, codon pair usage, dinucleotide/junction dinucleotide usage, RNA structure around the frameshift region) in comparison with other members of the coronaviridae family of viruses, the overall human genome, and the transcriptome of specific human tissues such as lung, which are primarily targeted by the virus. Our analysis identified the spike (S) and nucleocapsid (N) proteins as promising targets for deoptimization and suggests a roadmap for SARS-CoV-2 vaccine development, which can be generalizable to other viruses.

bioinformatics↗