BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
Autor: | Mai Huynh, Jekaterina Vohhodina, Vladimir V. Botchkarev, Elodie Hatchi, Fieda Abderazzaq, Scott B. Ficarro, Zhiqi Liu, Qing Kong, Jarrod A. Marto, Liana Goehring, Ben Liu, David M. Livingston, Allison P. Clark |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Genome instability endocrine system diseases R-loop General Physics and Astronomy medicine.disease_cause Mass Spectrometry chemistry.chemical_compound 0302 clinical medicine RNA Small Interfering Promoter Regions Genetic skin and connective tissue diseases In Situ Hybridization Fluorescence Mutation Multidisciplinary BRCA1 Protein Cell Cycle Telomere Chromatin Cell biology Telomeres 030220 oncology & carcinogenesis RNA Long Noncoding RNA Helicases Protein Binding Genomic instability Chromatin Immunoprecipitation DNA repair Science Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor medicine Humans DNA Helicases RNA Promoter General Chemistry Shelterin Multifunctional Enzymes 030104 developmental biology chemistry Exoribonucleases Long non-coding RNAs CpG Islands Fragile sites R-Loop Structures DNA Chromatography Liquid DNA Damage |
Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021) Nature Communications |
ISSN: | 2041-1723 |
Popis: | R-loop structures act as modulators of physiological processes such as transcription termination, gene regulation, and DNA repair. However, they can cause transcription-replication conflicts and give rise to genomic instability, particularly at telomeres, which are prone to forming DNA secondary structures. Here, we demonstrate that BRCA1 binds TERRA RNA, directly and physically via its N-terminal nuclear localization sequence, as well as telomere-specific shelterin proteins in an R-loop-, and a cell cycle-dependent manner. R-loop-driven BRCA1 binding to CpG-rich TERRA promoters represses TERRA transcription, prevents TERRA R-loop-associated damage, and promotes its repair, likely in association with SETX and XRN2. BRCA1 depletion upregulates TERRA expression, leading to overly abundant TERRA R-loops, telomeric replication stress, and signs of telomeric aberrancy. Moreover, BRCA1 mutations within the TERRA-binding region lead to an excess of TERRA-associated R-loops and telomeric abnormalities. Thus, normal BRCA1/TERRA binding suppresses telomere-centered genome instability. BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner. |
Databáze: | OpenAIRE |
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