Biology subjects

Masser, S.

Publications and source records attributed to Masser, S..

4 recordsLinked to original sources

bioRxiv2025

The cytosolic PRMT5-CDK4 complex impairs cell cycle kinase signaling

Both, protein arginine methyltransferases (PRMTs) and protein kinases are critical regulators of cellular processes and frequently dysregulated in malignancy. To systematically study the crosstalk of the two regulatory enzyme classes, we used parallel yeast two-hybrid matrix screening and defined 45 interactions connecting 4 PRMTs and 20 human kinases. The PRMT-kinase network revealed a strong association between PRMTs and cell cycle/mitogen-activated kinases. Notably, the PRMT5-CDK4 emerged as the most prominent functional cell cycle link through integrative data analyses of different high-throughput datasets. Mechanistic cell biological studies confirmed that the PRMT5-CDK4 complex localizes exclusively in the cytosol, where its formation was enhanced during a G1/S cell cycle block. This PRMT5 interaction modulated the CDK4-CCND3 and CDK4-CDKN2A interaction dynamics, irrespective of PRMT5s methyltransferase activity. Phospho-proteomic profiling demonstrated that PRMT5 overexpression functionally phenocopies the signaling effects of pharmacological CDK4 inhibition with Palbociclib. The findings establish a non-enzymatic regulatory role for PRMT5, proposing it functions as an inhibitory modulator of CDK4-driven oncogenic signaling.

systems biology↗

bioRxiv2025

Dissecting the role of RNA-binding proteins in early herpes simplex virus 1 transcription using acute protein depletion

Herpes simplex virus 1 (HSV-1) infects about 50-80% of the entire human population and persists in the neurons of affected individuals. A fraction of affected individuals suffer from recurrent cold sores caused by reactivating virus, in rare but severe cases the virus can cause encephalitis. During lytic infection, the virus relies on host factors such as RNA polymerase II and accessory proteins involved in transcription to express its genes and ensure successful replication. In general, RNA molecules in cells are bound by RNA-binding proteins (RBPs) during their entire lifecycle. Importantly, RBPs are increasingly described to also regulate transcription, an aspect long time outside the scope of investigations, especially during viral infections. Here, we examined the impact of five nuclear proteins (FUBP1, SLBP, SFPQ, SPT5 and SAF-B) with known RNA-binding activities on HSV-1 transcription. Additionally, we evaluated their importance for human adenovirus C5 (HAdV) growth to assess whether these host factors are specific to HSV-1 infections or might have broader relevance for the general transcription of dsDNA viruses. We show that the transcriptional elongation factor SPT5 coded by SUPT5H accumulates on HSV-1 genomes early during the infection and is required for the transcription of the immediate-early gene UL54. Its depletion affects also HAdV replication, indicating a general role in transcription of viruses that depend on the host transcriptional machinery. In contrast, depletion of the transcriptional repressor and paraspeckle protein SFPQ reduces UL54 RNA levels in HSV-1 infection, but does not cause significant changes in HAdV growth. Since SFPQ does not co-localize with HSV-1 genomes, this suggests a function not directly associated to viral DNA.

molecular biology↗

bioRxiv2024

Recurrent innovation of protein-protein interactions in the Drosophila piRNA pathway

Despite being essential for fertility, genome defence pathway genes often evolve rapidly. However, little is known about the molecular basis of this adaptation. Here, we characterize the evolution of a protein interaction network within the PIWI-interacting small RNA (piRNA) genome defence pathway in Drosophila at unprecedented scale and evolutionary resolution. We uncover pervasive rapid evolution of a protein interaction network anchored at the Heterochromatin Protein 1 (HP1) paralog Rhino. Using complementary phylogenetic analysis, high-throughput yeast-two-hybrid matrix screening, and in vivo interaction analyses in cross-species transgenic flies, we characterized three distinct evolutionary protein interaction trajectories across [~]40 million years of Drosophila evolution. The data set covering 11 piRNA pathway proteins of five Drosophila species revealed several protein interactions that are fully conserved, indicating functional conservation despite overall rapid amino acid sequence change. Other interactions are preserved through co-evolution and were detected only between proteins within or from closely related species. We also identified sets of species-restricted protein interactions which, through rewiring of a Rhino-anchored transcription factor network, may preserve critical roles in enabling and adapting piRNA production from heterochromatic loci. In sum, our analyses dissected principles of interaction evolution in an adaptively evolving protein-protein interaction network uncovering evolutionary and functional insight into germline piRNA production across Drosophila species. Our work provides key experimental evidence in support of a model proposing that intermolecular interaction innovation is a major molecular mechanism of evolutionary adaptation in protein-coding genes.

molecular biology↗

bioRxiv2023

Modulation of human kinase activity through direct interaction with SARS-CoV-2 proteins

The dysregulation of cellular signaling upon SARS-CoV-2 infection is mediated via direct protein interactions, with the human protein kinases constituting the major impact nodes in the signaling networks. Here, we employed a targeted yeast two-hybrid matrix approach to identify direct SARS-CoV-2 protein interactions with an extensive set of human kinases. We discovered 51 interactions involving 14 SARS-CoV-2 proteins and 29 human kinases, including many of the CAMK and CMGC kinase family members, as well as non-receptor tyrosine kinases. By integrating the interactions identified in our screen with transcriptomics and phospho-proteomics data, we revealed connections between SARS-CoV-2 protein interactions, kinase activity changes, and the cellular phospho-response to infection and identified altered activity patterns in infected cells for AURKB, CDK2, CDK4, CDK7, ABL2, PIM2, PLK1, NEK2, TRIB3, RIPK2, MAPK13, and MAPK14. Finally, we demonstrated direct inhibition of the FER human tyrosine kinase by the SARS-CoV-2 auxiliary protein ORF6, hinting at pressures underlying ORF6 changes observed in recent SARS-CoV-2 strains. Our study expands the SARS-CoV-2 - host interaction knowledge, illuminating the critical role of dysregulated kinase signaling during SARS-CoV-2 infection.

biochemistry↗