دورية أكاديمية

R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability.

التفاصيل البيبلوغرافية
العنوان: R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability.
المؤلفون: Mosler T; Institute of Molecular Biology (IMB), Mainz, Germany., Conte F; Institute of Molecular Biology (IMB), Mainz, Germany., Longo GMC; Institute of Molecular Biology (IMB), Mainz, Germany., Mikicic I; Institute of Molecular Biology (IMB), Mainz, Germany., Kreim N; Institute of Molecular Biology (IMB), Mainz, Germany., Möckel MM; Institute of Molecular Biology (IMB), Mainz, Germany., Petrosino G; Institute of Molecular Biology (IMB), Mainz, Germany., Flach J; Department of Hematology and Oncology, Medical Faculty Mannheim of the Heidelberg University, Mannheim, Germany., Barau J; Institute of Molecular Biology (IMB), Mainz, Germany., Luke B; Institute of Molecular Biology (IMB), Mainz, Germany.; Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität, Mainz, Germany., Roukos V; Institute of Molecular Biology (IMB), Mainz, Germany., Beli P; Institute of Molecular Biology (IMB), Mainz, Germany. p.beli@imb-mainz.de.; Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität, Mainz, Germany. p.beli@imb-mainz.de.
المصدر: Nature communications [Nat Commun] 2021 Dec 16; Vol. 12 (1), pp. 7314. Date of Electronic Publication: 2021 Dec 16.
نوع المنشور: Journal Article; 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: Genomic Instability* , Proteomics* , R-Loop Structures*/genetics , Transcription, Genetic*, DEAD-box RNA Helicases/*genetics , DEAD-box RNA Helicases/*metabolism, Adult ; Cell Line, Tumor ; DNA/metabolism ; DNA Breaks, Double-Stranded ; Gene Knockdown Techniques ; Genes, Tumor Suppressor ; HEK293 Cells ; Humans ; Leukemia, Myeloid, Acute ; Nucleic Acid Conformation ; Nucleic Acid Hybridization ; Promoter Regions, Genetic ; RNA/metabolism
مستخلص: Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA-DNA hybrid with a displaced non-template DNA strand. We developed RNA-DNA Proximity Proteomics to map the R-loop proximal proteome of human cells using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in promoters. DDX41 is enriched in promoter regions in vivo, and can unwind RNA-DNA hybrids in vitro. R-loop accumulation upon loss of DDX41 is accompanied with replication stress, an increase in the formation of double strand DNA breaks and transcriptome changes associated with the inflammatory response. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia in adulthood. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41.
(© 2021. The Author(s).)
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المشرفين على المادة: 63231-63-0 (RNA)
9007-49-2 (DNA)
EC 3.6.1.- (DDX41 protein, human)
EC 3.6.4.13 (DEAD-box RNA Helicases)
تواريخ الأحداث: Date Created: 20211217 Date Completed: 20211229 Latest Revision: 20230210
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8677849
DOI: 10.1038/s41467-021-27530-y
PMID: 34916496
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-021-27530-y