Distinct mechanisms of recognition of phosphorylated RNAPII C-terminal domain by BRCT repeats of the BRCA1–BARD1 complex

TL;DR

This study explores how the BRCA1-BARD1 complex interacts with RNA polymerase II to coordinate transcription and DNA repair processes.

Contribution

The paper reveals a novel mechanism by which BRCA1-BARD1 recognizes phosphorylated RNAPII, linking transcription and DNA repair.

Findings

The BRCA1 BRCT domain binds the Ser5-phosphorylated CTD of RNAPII using a known mechanism.

This interaction is essential for organizing RNAPII into liquid-like condensates.

Disease-associated BRCT variants affect this condensation, highlighting its biological importance.

Abstract

Transcription competes with other DNA-dependent processes, such as DNA repair, for access to its substrate, DNA. However, the principles governing the interplay between these processes remain poorly understood. Evidence suggests that the BRCA1-BARD1 complex, a key player in the DNA damage response, may act as a mediator of this crosstalk. In this study, we investigated the molecular mechanism underpinning the interaction between RNA polymerase II (RNAPII) and the BRCA1-BARD1 complex, as well as its functional implications. Our findings reveal that the tandem BRCT domain of BRCA1 binds the Ser5-phosphorylated CTD of RNAPII, utilizing a mechanism previously established for other BRCA1 BRCT ligands. Furthermore, we demonstrate that this interaction is critical for the organization of RNAPII into condensates with liquid-like properties. Analysis of disease-associated variants within the BRCT repeats further supports the biological relevance of this condensation. Collectively, our results suggest that the BRCA1-BARD1 complex may coordinate transcription and DNA repair by facilitating the organization of RNAPII into transcription factories.

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