TY - JOUR
T1 - BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
AU - Vohhodina, Jekaterina
AU - Goehring, Liana J.
AU - Liu, Ben
AU - Kong, Qing
AU - Botchkarev, Vladimir V.
AU - Huynh, Mai
AU - Liu, Zhiqi
AU - Abderazzaq, Fieda O.
AU - Clark, Allison P.
AU - Ficarro, Scott B.
AU - Marto, Jarrod A.
AU - Hatchi, Elodie
AU - Livingston, David M.
N1 - Funding Information:
We wish to thank Dr. Shailja Pathania (UMass Boston) for providing HME cells. We thank all members of the Livingston group and Dr. David Pellman (Dana-Farber Cancer Institute) for their very helpful advice. We are also grateful to Dr. Joan Brugge and members of her group and to Drs. Myles Brown, Kornelia Polyak, and Robert Weinberg for their valuable suggestions. This work was supported by grants from the National Cancer Institute/NIH-Mechanisms of Breast Development and Carcinogenesis (P01CA080111), BRCA1 Function in Post Damage Foci (R01CA136512), Deciphering the Mechanism Underlying BRCA1 Breast Cancer Development (5R35CA242143-02), the Gray Foundation, the Breast Cancer Research Foundation (BCRF-19-101), The Susan G Komen Foundation for the Cure (SAC140022), the BRCA Foundation, Evan M. and Cynthia Goldberg, and the Murray Winston Foundation.
Publisher Copyright:
© 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-23716-6
DO - 10.1038/s41467-021-23716-6
M3 - Article
C2 - 34112789
AN - SCOPUS:85107527341
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3542
ER -