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
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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