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The 9-1-1 complex protects ssDNA gaps in BRCA2-deficient cancer
Helen E Grimsley1,2, Katherine Courtemanche1,2, Shane Cox1,2
1Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
The RAD9A-HUS1-RAD1 (9-1-1) complex is crucial for BRCA2-deficient cells
Area of Science:
- DNA repair mechanisms
- Genomic instability in cancer
Background:
- Single-stranded DNA (ssDNA) gaps are characteristic of BRCA-deficient cells.
- The precise mechanisms protecting these ssDNA gaps are not fully understood.
Purpose of the Study:
- To identify key regulators of ssDNA gap stability in BRCA2-deficient cells.
- To elucidate the role of the 9-1-1 complex in DNA repair pathways.
Main Methods:
- Genome-wide CRISPR screening to identify essential genes.
- Analysis of DNA damage accumulation and repair pathways.
- Gene depletion experiments (e.g., EXO1 depletion).
Main Results:
- The RAD9A-HUS1-RAD1 (9-1-1) complex is vital for BRCA2-deficient cell survival via an ATR-independent pathway.
- Loss of 9-1-1 leads to PRIMPOL-dependent ssDNA gap expansion and increased DNA damage.
- EXO1-mediated degradation drives instability, and its depletion rescues the phenotype.
- The 9-1-1 complex is necessary for POLζ-dependent gap filling.
Conclusions:
- The 9-1-1 complex is a critical regulator of ssDNA gap stability.
- Findings suggest the 9-1-1 complex is a potential therapeutic target for BRCA2-deficient cancers.
Keywords:
9-1-1 complexATRBRCA1/BRCA2EXO1 synthetic lethalPOLζPRIMPOLgap protectionhomologous recombinationreplication gapsssDNAtranslesion synthesisMore Related Videos
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