RNF8 ubiquitylation of XRN2 facilitates R-loop resolution and restrains genomic instability in BRCA1 mutant cells

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Breast cancer with BRCA1/2 mutations often recurs and resists therapies like PARP inhibitors.
• Effective targeted therapies for BRCA1-mutant breast cancers are lacking.
• RNF8 deficiency shows protective effects in Brca1-mutant mouse models.

Purpose of the Study:

• To identify novel therapeutic targets for BRCA1-mutant breast cancers.
• To investigate the role of RNF8 in BRCA1-mutant mammary tumorigenesis.
• To elucidate the mechanism underlying RNF8's effect on cancer cell survival.

Main Methods:

• Investigated RNF8 deficiency in BRCA1-mutant breast cancer cells and mouse models.
• Analyzed R-loop accumulation, replication fork stability, and DNA damage.
• Examined the interaction between RNF8 and XRN2 in transcription termination and R-loop resolution.

Main Results:

• RNF8 deficiency promotes R-loop accumulation and replication fork instability in BRCA1-mutant cells.
• This leads to increased DNA damage, senescence, and synthetic lethality.
• RNF8 ubiquitylates XRN2, facilitating its recruitment to R-loop sites; deficiency impairs this, causing pathological R-loop accumulation.

Conclusions:

• Identified a synthetic lethal interaction between RNF8 and BRCA1 in breast cancer.
• RNF8 deficiency induces cancer cell death via R-loop accumulation and genomic instability.
• Targeting RNF8 represents a potential therapeutic strategy for BRCA1-mutant breast cancers.