Biology subjects

Kaya, O.

Publications and source records attributed to Kaya, O..

3 recordsLinked to original sources

bioRxiv2023

Identification of astrocyte-driven pseudolineages reveals clinical stratification and therapeutic targets in Glioblastoma

The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecast how tumor cells organize to sustain growth and identifies rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA-related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt-antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumors stem-like methylome into an astrocyte-like one. Our findings offer a novel patient stratification with clinical impact, new biomarkers and therapeutic avenues to halt GBM progression.

cancer biology↗

bioRxiv2023

Aurora B Kinase Dependent Phosphorylation of Keratin 8 is required for Cytokinesis in Mammalian Cells of Epithelial Origin

Keratins assemble into mechanically resilient polymers that physically stabilize epithelial cells. When epithelial cells divide, keratin polymers must be severed to allow cell separation during cytokinesis. Phosphorylation has been implicated in this process, but how keratins are regulated during cell division is not understood. Aurora-B kinase, which is part of the chromosome passenger complex (CPC) accumulates at the cell center during cytokinesis and has been implicated in regulating intermediate filaments. We mapped six Aurora B kinase sites in Keratin 8. Phosphorylation of Keratin 8 at S34 occurred specifically at the cleavage furrow and persisted at the midzone until the completion of cytokinesis. Inhibition of Aurora B or expression of a non-phosphorylatable Keratin 8 mutant impaired keratin disassembly at the cleavage furrow. We propose that Aurora B-mediated phosphorylation promotes localized keratin filament disassembly at the cleavage furrow, allowing spatially regulated disassembly during cytokinesis. Aurora B binds to keratin filaments, and its localization to midzones was reduced in Keratin 8 knockout cells, showing that Keratin 8 facilitates Aurora B targeting during cytokinesis. This suggests a positive feedback cycle whereby Keratin 8 promotes midzone-localization of Aurora B and in turn, is locally disassembled by its kinase activity. This cycle is required for successful furrow ingression and completion of cell division in cancer cells of epithelial origin and might provide a target for solid tumor treatment.

cell biology↗

bioRxiv2020

Comparative analyses of two primate species diverged by more than 60 million years show different rates but similar distribution of genome-wide UV repair events

Nucleotide excision repair is the primary DNA repair mechanism that removes bulky DNA adducts such as UV-induced pyrimidine dimers. Correspondingly, genome-wide mapping of nucleotide excision repair with eXcision Repair sequencing (XR-seq), provides comprehensive profiling of DNA damage repair. A number of XR-seq experiments at a variety of conditions for different damage types revealed heterogenous repair in the human genome. Although human repair profiles were extensively studied, how repair maps vary between primates is yet to be investigated. Here, we characterized the genome-wide UV-induced damage repair in gray mouse lemur, Microcebus murinus, in comparison to human. Mouse lemurs are strictly nocturnal, are the worlds smallest living primates, and last shared a common ancestor with humans at least 60 million years ago. We derived fibroblast cell lines from mouse lemur, exposed them to UV irradiation. The following repair events were captured genome-wide through the XR-seq protocol. Mouse lemur repair profiles were analyzed in comparison to the equivalent human fibroblast datasets. We found that overall UV sensitivity, repair efficiency, and transcription-coupled repair levels differ between the two primates. Despite this, comparative analysis of human and mouse lemur fibroblasts revealed that genome-wide repair profiles of the homologous regions are highly correlated. This correlation is stronger for the highly expressed genes. With the inclusion of an additional XR-seq sample derived from another human cell line in the analysis, we found that fibroblasts of the two primates repair UV-induced DNA lesions in a more similar pattern than two distinct human cell lines do. Our results suggest that mouse lemurs and humans, and possibly primates in general, share a homologous repair mechanism as well as genomic variance distribution, albeit with their variable repair efficiency. This result also emphasizes the deep homologies of individual tissue types across the eukaryotic phylogeny.

genomics↗