Biology subjects

Kolmus, K.

Publications and source records attributed to Kolmus, K..

3 recordsLinked to original sources

bioRxiv2022

SLIDE-VIP: a comprehensive, cell line- and patient-based framework for synthetic lethality prediction in DNA damage repair, chromatin remodeling and cell cycle

Discovering synthetic lethal (SL) gene partners of cancer genes is an important step in developing cancer therapies. However, identification of SL interactions is challenging, due to a large number of possible gene pairs, inherent noise and confounding factors in the observed signal. To discover robust SL interactions, we devised SLIDE-VIP, a novel framework combining eight statistical tests, including a new patient data-based test iSurvLRT. SLIDE-VIP leverages multi-omics data from four different sources: gene inactivation cell line screens, cancer patient data, drug screens and gene pathways. We applied SLIDE-VIP to discover SL interactions between genes involved in DNA damage repair, chromatin remodeling and cell cycle, and their potentially druggable partners. The top 883 ranking SL candidates had strong evidence in cell line and patient data, 250-fold reducing the initial space of 200K pairs. Drug screen and pathway tests provided additional corroboration and insights into these interactions. We rediscovered well-known SL pairs such as RB1 and E2F3 or PRKDC and ATM, and in addition, proposed strong novel SL candidates such as PTEN and PIK3CB. In summary, SLIDE-VIP opens the door to the discovery of SL interactions with clinical potential. All analysis and visualizations are available via the online SLIDE-VIP WebApp.

bioinformatics↗

bioRxiv2021

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling.

Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of proteins residing in endosomal membranes. Recent studies revealed that yeast ESCRT machinery also sorts ubiquitinated proteins from the vacuolar membrane for degradation in the vacuole lumen. However, whether mammalian ESCRTs perform a similar function at lysosomes remained unknown. Here, we show that ESCRT-I restricts the size of lysosomes and promotes degradation of proteins from lysosomal membranes, including MCOLN1, a Ca2+ channel protein. Upon ESCRT-I depletion, the lysosomal accumulation of non-degraded proteins coincided with elevated expression of genes annotated to cholesterol biosynthesis and biogenesis of lysosomes, indicative of response to lysosomal stress. Accordingly, the lack of ESCRT-I promoted abnormal cholesterol accumulation in lysosomes and activated TFEB/TFE3 transcription factors. Finally, we discovered that in contrast to basal TFEB/TFE3 signaling that depended on the availability of exogenous lipids, the stress-induced activation of this pathway was Ca2+-MCOLN1-dependent. Hence, we provide evidence that ESCRT-I is crucial for maintaining lysosomal homeostasis and we elucidate mechanisms distinguishing basal from lysosomal stress-induced TFEB/TFE3 signaling.

cell biology↗

bioRxiv2020

Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses

ABSTRACTMolecular details of how endocytosis contributes to oncogenesis remain elusive. Our in silico analysis of colorectal cancer (CRC) patients revealed stage-dependent alterations in the expression of 113 endocytosis-related genes. Among them transcription of the Endosomal Sorting Complex Required for Transport (ESCRT)-I component VPS37B was decreased in the advanced stages of CRC. Expression of other ESCRT-I core subunits remained unchanged in the investigated dataset. We analyzed an independent cohort of CRC patients showing also reduced VPS37A mRNA and protein abundance. Transcriptomic profiling of CRC cells revealed non-redundant functions of Vps37 proteins. Knockdown of VPS37A and VPS37B triggered p21-mediated inhibition of cell proliferation and sterile inflammatory response driven by the Nuclear Factor (NF)-κB transcription factor and associated with mitogen-activated protein kinase signaling. Co-silencing of VPS37C further potentiated activation of these independently induced processes. The type and magnitude of transcriptional alterations correlated with the differential ESCRT-I stability upon individual and concurrent Vps37 depletion. Our study provides novel insights into cancer cell biology by describing cellular stress responses that are associated with ESCRT-I destabilization, which might occur in CRC patients.SUMMARY STATEMENT Endosomal Sorting Complex Required for Transport (ESCRT)-I destabilization upon concurrent depletion of Vps37 proteins is linked to the activation of sterile inflammatory response and cell growth inhibition.View Full Text

cell biology↗