The Cancer Dependency Map (DepMap)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1027967 | ENA |
REPOSITORIES: ENA
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Project description:The Cancer Dependency Map (DepMap)
| PRJNA1027968 | ENA
Project description: Not available
| S-EPMC5667678 | biostudies-literature
Project description:Short linear motifs (SLiMs) are the most ubiquitous protein interaction modules in the unstructured regions of the human proteome. Despite their central role in protein function, our understanding of the contribution of SLiMs to cellular homeostasis remains limited. To address this, we designed base editor libraries to precisely mutate all curated SLiMs and a set of computationally predicted instances defined by SLiM-like evolutionary patterns. By targeting 7,293 SLiM containing regions with 80,473 mutations, we define an amino acid resolution SLiM dependency map identifying 450 known and 264 predicted SLiMs required for normal cell proliferation. Notably, the vast majority of essential predicted SLiMs belong to novel classes of SLiMs. We also uncover the functions of several predicted SLiMs in core biological processes and provide mechanistic insight into disease causing mutations. Collectively, our study provides a proteome-wide publicly accessible resource on SLiM essentiality and highlights the presence of numerous uncharacterised essential SLiMs in the human proteome.
2026-01-14 | PXD055750 | Pride
Project description:A prostate cancer chromatin interaction map
| PRJNA486278 | ENA
Project description: Not available
| S-EPMC8049517 | biostudies-literature
Project description: Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse human proteins. Determining which of these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cancer cell proliferation. The resulting atlas, which covers >13,800 cysteines on >1,750 cancer dependency proteins, confirms the essentiality of cysteines targeted by covalent drugs and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines in >110 cancer dependency proteins. We further show that a stereoselective and site-specific ligand targeting an essential cysteine in TOE1 inhibits the nuclease activity of this protein through an apparent allosteric mechanism. Our findings thus describe a versatile method and valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.
2023-09-06 | PXD041314 | Pride
Project description:Chemical probes are lacking for most human proteins. Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse proteins. Determining which of these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cell proliferation. We show that the resulting atlas, which covers >13,800 cysteines on >1,750 cancer dependency proteins, correctly predicts the essentiality of cysteines targeted by cancer therapeutics and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines on >110 cancer dependency proteins. We finally demonstrate how measurements of reactivity in native versus denatured proteomes can further discriminate essential cysteines amendable to chemical modification from those buried in protein structures, providing a valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.
2023-09-06 | PXD038239 | Pride
Project description:Chemical probes are lacking for most human proteins. Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse proteins. Determining which of these covalent binding events impact protein function, however, remains challenging. Here, we describe a base-editing strategy to infer the functionality of cysteines by quantifying the impact of their missense mutation on cell proliferation. We show that the resulting atlas, which covers >13,800 cysteines on >1,750 cancer dependency proteins, correctly predicts the essentiality of cysteines targeted by cancer therapeutics and, when integrated with chemical proteomic data, identifies essential, ligandable cysteines on >110 cancer dependency proteins. We finally demonstrate how measurements of reactivity in native versus denatured proteomes can further discriminate essential cysteines amendable to chemical modification from those buried in protein structures, providing a valuable resource to prioritize the pursuit of small-molecule probes with high function-perturbing potential.
2023-09-06 | PXD038232 | Pride
Project description:Incomplete paralog compensation generates selective dependency on TRA2A in cancer
| PRJNA1251972 | ENA
Project description:TRPS1 is a lineage-specific transcriptional dependency in breast cancer
| PRJNA471878 | ENA