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

## TL;DR

BRCA1 helps prevent DNA damage at telomeres by binding to TERRA RNA and resolving R-loops, which is important for maintaining genome stability.

## Contribution

The novel finding is that BRCA1 directly binds TERRA RNA at telomeres in a cell cycle- and R-loop-dependent manner to suppress telomeric DNA damage.

## Key findings

- BRCA1 binds TERRA RNA and telomere-specific shelterin proteins in an R-loop- and cell cycle-dependent manner.
- BRCA1 represses TERRA transcription and prevents TERRA R-loop-associated damage, likely through interaction with SETX and XRN2.
- BRCA1 depletion or mutations in its TERRA-binding region lead to increased TERRA R-loops and telomeric abnormalities.

## 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.

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.