Biology subjects

Schwarzer, A.

Publications and source records attributed to Schwarzer, A..

4 recordsLinked to original sources

bioRxiv2026

Queuosine glycosylation protects against stress-induced tRNA fragmentation and modulates cleavage site selection

Alongside their canonical function as adaptors in translation, tRNAs are precursors of tRNA-derived fragments that can regulate diverse aspects of gene expression. Queuosine (Q), present at position 34 of eukaryotic tRNAAsn/Asp/His/Tyr, has been implicated in suppressing tRNA fragmentation. In vertebrates, Q34 of tRNAAsp and tRNATyr is further modified by mannosylation and galactosylation, respectively, catalyzed by QTMAN and QTGAL. However, the interplay between these glycosylations and other anticodon loop modifications, and their impact on tRNA fragmentation, have remained unclear. Here, we define a modification circuit in human tRNAAsp in which Q34 stimulates DNMT2-dependent m5C38 formation, while subsequent Q34 mannosylation does not impact m5C38 installation; reciprocally, m5C38 inhibits Q34 incorporation by the tRNA-guanine transglycosylase TGT. By contrast, anticodon loop modifications of tRNATyr are installed independently, although our data support a hierarchical pathway in which TRMT5-mediated m1G37 formation precedes queuosinylation and galactosylation. Alongside demonstrating that Q34 glycosylation enhances protein synthesis, our data reveal that mannosylation of Q34 protects tRNAAsp from stress-induced cleavage, thus expanding the relevance of Q glycosylation beyond translation.

Molecular Biology↗

bioRxiv2024

Circulation of West Nile Virus and Usutu Virus in Birds in Germany, 2021 and 2022.

BackgroundUsutu virus (USUV) and West Nile virus (WNV) are zoonotic arthropod-borne orthoflaviviruses. The enzootic transmission cycles of both include Culex mosquitoes as vectors and birds as amplifying hosts. For more than ten years, these viruses have been monitored in birds in Germany by a multidisciplinary network. While USUV is present nationwide, WNV used to be restricted to the central-east. MethodsIn 2021 and 2022, over 2300 live bird blood samples and organs from over 3000 deceased birds were subjected to molecular and serological analysis regarding presence of WNV and USUV. The samples were collected at sites all over Germany. ResultsCirculation of both viruses increased in 2022. For USUV, the nationwide presence of lineages Africa 3 and Europe 3 reported in previous years was confirmed. Lineage Europe 2, formerly restricted to the German east, was able to expand westward. Nonetheless, USUV neutralizing antibody (nAb) detection rates remained low (< 9%). 2021 and 2022 were characterized by stable enzootic circulation of WNV lineage 2, dominated by one previously identified subcluster (95% of generated sequences). In 2022, more than 20% of birds in the endemic region in eastern Germany carried nAb against WNV. Serological data also indicate expanding WNV circulation west and south of the known hotspots in Germany. ConclusionsUSUV circulates enzootically nationwide. Emergence of WNV at several new locations in Germany with a potential increase in human infections may be imminent. In this context, wild bird monitoring serves as a capable early-warning system in a One Health setting.

microbiology↗

bioRxiv2022

Pharmacological activation of the mitochondrial stress protease OMA1 reveals a therapeutic liability in Diffuse Large B-Cell Lymphoma

Constitutive activation of the ATF4-mediated integrated stress response (ATF4-ISR) is common in cancer and buffers the metabolic challenges imposed by rapid proliferation. However, hyperactivation of the ISR can induce apoptosis. Here we demonstrate that novel pyrazolo-thiazole derivates activate the mitochondrial protease OMA1 which subsequently induces apoptosis in diffuse large B-cell lymphoma (DLBCL) cells. Apoptosis is dependent on the OMA1 mediated cleavage of DELE1 which leads to activation of HRI and induction of the ATF4 ISR. Screening in 406 cancer cell lines identified an inverse correlation between sensitivity to OMA1 activators and expression of the mitochondrial protein FAM210B. Ectopic overexpression of FAM210B specifically blocks OMA1 activation and apoptosis induction by pyrazolo-thiazole activators in DLBCL. OMA1 activators, including the preclinical candidate BTM-3566, selectively killed ABC, GCB, and double-hit DLBCL lines and induced complete tumor regression across a panel of DLBCL patient-derived xenografts. SignificanceHere we describe a novel class of small molecules that activate the mitochondrial protease OMA1 and induce therapeutic responses in DLBCL preclinical models in vitro and in vivo. OMA1 activation drives apoptosis through ATF4-ISR, an orthogonal mechanism to current therapies.

cancer biology↗

bioRxiv2020

Reprogramming enriches for somatic cell clones with small scale mutations in cancer-associated genes

Recent studies demonstrated that the mutational load in human induced pluripotent stem cells (hiPSCs) is largely derived from their parental cells, but it is still unknown whether reprogramming may enrich for individual mutations. 30 hiPSC lines were analyzed by whole exome sequencing. High accuracy amplicon sequencing showed that all analyzed small scale variants pre-existed in their parental cells and that individual mutations present in small subpopulations of parental cells become enriched among hiPSC clones during reprogramming. Among those, putatively actionable driver mutations affect genes related to cell cycle control, cell death and pluripotency, and may confer a selective advantage during reprogramming. Finally, a shRNA-based experimental approach was applied to provide additional evidence for the individual impact of such genes on the reprogramming efficiency. In conclusion, we show that enriched mutations in curated onco- and tumor suppressor genes may account for an increased tumor risk and impact the clinical value of patient-derived hiPSCs.

genomics↗