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BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage.
Vohhodina, Jekaterina; Goehring, Liana J; Liu, Ben; Kong, Qing; Botchkarev, Vladimir V; Huynh, Mai; Liu, Zhiqi; Abderazzaq, Fieda O; Clark, Allison P; Ficarro, Scott B; Marto, Jarrod A; Hatchi, Elodie; Livingston, David M.
Afiliación
  • Vohhodina J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. jekaterina_vohhodina@dfci.harvard.edu.
  • Goehring LJ; Department of Genetics, Harvard Medical School, Boston, MA, USA. jekaterina_vohhodina@dfci.harvard.edu.
  • Liu B; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Kong Q; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Botchkarev VV; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Huynh M; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Liu Z; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Abderazzaq FO; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Clark AP; Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Ficarro SB; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Marto JA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Hatchi E; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Livingston DM; Department of Genetics, Harvard Medical School, Boston, MA, USA.
Nat Commun ; 12(1): 3542, 2021 06 10.
Article en En | MEDLINE | ID: mdl-34112789
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / Telómero / Proteína BRCA1 / ARN Largo no Codificante / Estructuras R-Loop Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Daño del ADN / Telómero / Proteína BRCA1 / ARN Largo no Codificante / Estructuras R-Loop Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido