BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage

• Published in: Nature communications Vol. 12; no. 1; p. 3542
• Main Authors: Vohhodina, Jekaterina, Goehring, Liana J., Liu, Ben, Kong, Qing, Botchkarev Jr, Vladimir V., Huynh, Mai, Liu, Zhiqi, Abderazzaq, Fieda O., Clark, Allison P., Ficarro, Scott B., Marto, Jarrod A., Hatchi, Elodie, Livingston, David M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/109; 38/15; 38/32; 38/77; 38/90; 631/208/737/211; 631/337/100; 631/337/103/560; 631/337/151/2357; 631/337/384/2568; 82/1; 82/83; Abnormalities; Binding; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Breast cancer; Cell cycle; Cell Cycle - genetics; Cell Line, Tumor; Chromatin Immunoprecipitation; Chromatography, Liquid; CpG Islands; Damage prevention; Deoxyribonucleic acid; Depletion; DNA; DNA damage; DNA Damage - genetics; DNA Helicases - metabolism; DNA repair; Exoribonucleases - metabolism; Gene regulation; Genomic instability; Humanities and Social Sciences; Humans; In Situ Hybridization, Fluorescence; Localization; Mass Spectrometry; Modulators; multidisciplinary; Multifunctional Enzymes - metabolism; Mutation; Nucleotide sequence; Promoter Regions, Genetic; Protein Binding; R-Loop Structures - genetics; R-loops; Repair; Replication; Ribonucleic acid; RNA; RNA Helicases - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Small Interfering; Science; Science (multidisciplinary); Structural damage; Telomere - genetics; Telomere - metabolism; Telomeres; Transcription termination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23716-6

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.