Chemoproteogenomic stratification of the missense variant cysteinome
Abstract Cancer genomes are rife with genetic variants; one key outcome of this variation is widespread gain-of-cysteine mutations. These acquired cysteines can be both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain u...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53520-x |
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| author | Heta Desai Katrina H. Andrews Kristina V. Bergersen Samuel Ofori Fengchao Yu Flowreen Shikwana Mark A. Arbing Lisa M. Boatner Miranda Villanueva Nicholas Ung Elaine F. Reed Alexey I. Nesvizhskii Keriann M. Backus |
| author_facet | Heta Desai Katrina H. Andrews Kristina V. Bergersen Samuel Ofori Fengchao Yu Flowreen Shikwana Mark A. Arbing Lisa M. Boatner Miranda Villanueva Nicholas Ung Elaine F. Reed Alexey I. Nesvizhskii Keriann M. Backus |
| author_sort | Heta Desai |
| collection | DOAJ |
| description | Abstract Cancer genomes are rife with genetic variants; one key outcome of this variation is widespread gain-of-cysteine mutations. These acquired cysteines can be both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain unidentified via chemoproteomics; identification is a critical step to enable functional analysis, including assessment of potential druggability and susceptibility to oxidation. Here, we pair cysteine chemoproteomics—a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues—with genomics to reveal the hidden landscape of cysteine genetic variation. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized two-stage false discovery rate (FDR) error controlled proteomic search, which is further enhanced with a user-friendly FragPipe interface. Chemoproteogenomics analysis reveals that cysteine acquisition is a ubiquitous feature of both healthy and cancer genomes that is further elevated in the context of decreased DNA repair. Reference cysteines proximal to missense variants are also found to be pervasive, supporting heretofore untapped opportunities for variant-specific chemical probe development campaigns. As chemoproteogenomics is further distinguished by sample-matched combinatorial variant databases and is compatible with redox proteomics and small molecule screening, we expect widespread utility in guiding proteoform-specific biology and therapeutic discovery. |
| format | Article |
| id | doaj-art-8497dd94edd44189a1d7fe0683afc5b4 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8497dd94edd44189a1d7fe0683afc5b42025-08-20T02:18:35ZengNature PortfolioNature Communications2041-17232024-10-0115112410.1038/s41467-024-53520-xChemoproteogenomic stratification of the missense variant cysteinomeHeta Desai0Katrina H. Andrews1Kristina V. Bergersen2Samuel Ofori3Fengchao Yu4Flowreen Shikwana5Mark A. Arbing6Lisa M. Boatner7Miranda Villanueva8Nicholas Ung9Elaine F. Reed10Alexey I. Nesvizhskii11Keriann M. Backus12Biological Chemistry Department, David Geffen School of Medicine, UCLABiological Chemistry Department, David Geffen School of Medicine, UCLADepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLABiological Chemistry Department, David Geffen School of Medicine, UCLADepartment of Pathology, University of MichiganBiological Chemistry Department, David Geffen School of Medicine, UCLABiological Chemistry Department, David Geffen School of Medicine, UCLABiological Chemistry Department, David Geffen School of Medicine, UCLABiological Chemistry Department, David Geffen School of Medicine, UCLABiological Chemistry Department, David Geffen School of Medicine, UCLADepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLADepartment of Pathology, University of MichiganBiological Chemistry Department, David Geffen School of Medicine, UCLAAbstract Cancer genomes are rife with genetic variants; one key outcome of this variation is widespread gain-of-cysteine mutations. These acquired cysteines can be both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain unidentified via chemoproteomics; identification is a critical step to enable functional analysis, including assessment of potential druggability and susceptibility to oxidation. Here, we pair cysteine chemoproteomics—a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues—with genomics to reveal the hidden landscape of cysteine genetic variation. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized two-stage false discovery rate (FDR) error controlled proteomic search, which is further enhanced with a user-friendly FragPipe interface. Chemoproteogenomics analysis reveals that cysteine acquisition is a ubiquitous feature of both healthy and cancer genomes that is further elevated in the context of decreased DNA repair. Reference cysteines proximal to missense variants are also found to be pervasive, supporting heretofore untapped opportunities for variant-specific chemical probe development campaigns. As chemoproteogenomics is further distinguished by sample-matched combinatorial variant databases and is compatible with redox proteomics and small molecule screening, we expect widespread utility in guiding proteoform-specific biology and therapeutic discovery.https://doi.org/10.1038/s41467-024-53520-x |
| spellingShingle | Heta Desai Katrina H. Andrews Kristina V. Bergersen Samuel Ofori Fengchao Yu Flowreen Shikwana Mark A. Arbing Lisa M. Boatner Miranda Villanueva Nicholas Ung Elaine F. Reed Alexey I. Nesvizhskii Keriann M. Backus Chemoproteogenomic stratification of the missense variant cysteinome Nature Communications |
| title | Chemoproteogenomic stratification of the missense variant cysteinome |
| title_full | Chemoproteogenomic stratification of the missense variant cysteinome |
| title_fullStr | Chemoproteogenomic stratification of the missense variant cysteinome |
| title_full_unstemmed | Chemoproteogenomic stratification of the missense variant cysteinome |
| title_short | Chemoproteogenomic stratification of the missense variant cysteinome |
| title_sort | chemoproteogenomic stratification of the missense variant cysteinome |
| url | https://doi.org/10.1038/s41467-024-53520-x |
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