LIG1 Is a Synthetic Lethal Target in BRCA1 Mutant Cancers.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Synthetic lethality strategies for BRCA1/2-mutated cancers often rely on PARP inhibitors, facing significant patient resistance.
• Identifying novel synthetic lethal targets is crucial for overcoming treatment resistance in these cancers.

Purpose of the Study:

• To identify and validate DNA ligase I (LIG1) as a novel synthetic lethal target in BRCA1-mutated cancers.
• To investigate the mechanism of LIG1's synthetic lethality in BRCA1-deficient cells.

Main Methods:

• CRISPR/Cas9 screening to identify synthetic lethal targets.
• In vitro validation using CRISPRn, CRISPRi, RNAi, and protein degradation to inactivate LIG1.
• Assessment of cell viability, LIG1 catalytic activity, and DNA damage markers (PAR staining).
• In vivo validation using a xenograft model.

Main Results:

• CRISPR screening identified DNA ligase I (LIG1) as a synthetic lethal target in BRCA1-mutated cancers.
• LIG1 inactivation selectively reduced viability in BRCA1-mutated cell lines but not in BRCA1/2 wild-type cells.
• LIG1's catalytic activity is essential for maintaining viability in BRCA1-mutated cells.
• LIG1 depletion in BRCA1-mutated cells led to increased DNA damage (PAR staining) and tumor stasis in vivo.

Conclusions:

• DNA ligase I (LIG1) is a promising, selective synthetic lethal target for BRCA1-mutated cancers.
• Targeting LIG1 offers a potential therapeutic strategy to overcome resistance to existing treatments like PARP inhibitors.