دورية أكاديمية

Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility.

التفاصيل البيبلوغرافية
العنوان: Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility.
المؤلفون: Ku AA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA., Hu HM; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA., Zhao X; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA., Shah KN; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA., Kongara S; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA., Wu D; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA., McCormick F; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA., Balmain A; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA., Bandyopadhyay S; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, 94158, USA. Sourav.bandyopadhyay@ucsf.edu.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, 94158, USA. Sourav.bandyopadhyay@ucsf.edu.
المصدر: Nature communications [Nat Commun] 2020 May 12; Vol. 11 (1), pp. 2375. Date of Electronic Publication: 2020 May 12.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Data Analysis* , Gene Regulatory Networks* , Synthetic Lethal Mutations*, Computational Biology/*methods , Neoplasms/*genetics, Animals ; BRCA1 Protein/genetics ; Cell Line, Tumor ; Computational Biology/standards ; Disease Models, Animal ; Humans ; Mice ; Protein Interaction Maps/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Reproducibility of Results
مستخلص: Synthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. In the case of KRAS, we identify that published synthetic lethal screen hits significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks could identify synthetic lethal candidates that are more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes are strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identifies numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework.
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معلومات مُعتمدة: R35 CA210018 United States CA NCI NIH HHS; U01 CA168370 United States CA NCI NIH HHS
المشرفين على المادة: 0 (BRCA1 Protein)
0 (BRCA1 protein, human)
0 (KRAS protein, human)
EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
تواريخ الأحداث: Date Created: 20200514 Date Completed: 20200831 Latest Revision: 20240329
رمز التحديث: 20240329
مُعرف محوري في PubMed: PMC7217969
DOI: 10.1038/s41467-020-16078-y
PMID: 32398776
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-020-16078-y