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

Jekaterina Vohhodina (), Liana J. Goehring, Ben Liu, Qing Kong, Vladimir V. Botchkarev, Mai Huynh, Zhiqi Liu, Fieda O. Abderazzaq, Allison P. Clark, Scott B. Ficarro, Jarrod A. Marto, Elodie Hatchi and David M. Livingston ()
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Jekaterina Vohhodina: Dana-Farber Cancer Institute
Liana J. Goehring: Dana-Farber Cancer Institute
Ben Liu: Dana-Farber Cancer Institute
Qing Kong: Dana-Farber Cancer Institute
Vladimir V. Botchkarev: Dana-Farber Cancer Institute
Mai Huynh: Dana-Farber Cancer Institute
Zhiqi Liu: Dana-Farber Cancer Institute
Fieda O. Abderazzaq: Dana-Farber Cancer Institute
Allison P. Clark: Dana-Farber Cancer Institute
Scott B. Ficarro: Dana-Farber Cancer Institute
Jarrod A. Marto: Dana-Farber Cancer Institute
Elodie Hatchi: Dana-Farber Cancer Institute
David M. Livingston: Dana-Farber Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23716-6

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