RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors

Area of Science:

• Molecular biology
• Cancer genetics
• Genomic instability

Background:

• Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes significantly elevate breast and ovarian cancer risk.
• BRCA1/2-mutant tumors exhibit genomic instability and are vulnerable to PARP inhibition, but underlying mechanisms are not fully understood.
• BRCA1 and BRCA2 are implicated in suppressing R-loops, DNA:RNA hybrid structures.

Purpose of the Study:

• To investigate the role of RNF168 in BRCA1/2-mutant tumorigenesis.
• To elucidate the molecular mechanisms by which RNF168 influences R-loop dynamics and cancer development.
• To identify potential therapeutic targets in BRCA1/2-defective cancers.

Main Methods:

• Studied Brca1-mutant mouse models.
• Assessed R-loop accumulation, DNA double-strand breaks (DSBs), and senescence in cancer cells.
• Utilized interactome assays to identify protein interactions.
• Investigated the ubiquitylation of DHX9 by RNF168.

Main Results:

• RNF168 deficiency protected Brca1-mutant mice against mammary tumors.
• RNF168 loss led to R-loop accumulation, DSBs, and cell death in BRCA1/2-mutant cancer cells.
• RNF168 interacts with DHX9, a helicase that resolves R-loops.
• RNF168 ubiquitylation of DHX9 facilitates its recruitment to R-loops; RNF168 loss impairs this recruitment and R-loop resolution.

Conclusions:

• RNF168 plays a critical role in promoting BRCA1/2-mutant tumorigenesis.
• BRCA1/2-defective tumors depend on R-loop suppressing factors.
• RNF168-mediated regulation of DHX9 and R-loop resolution is a key mechanism in cancer development and vulnerability.