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PTIP associates with Artemis to dictate DNA repair pathway choice
Jiadong Wang1, Asaithamby Aroumougame2, Markus Lobrich3
1Institute of Systems Biomedicine, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
Abstract:
PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1-interacting factor 1 homolog), lack enzymatic activities directly implicated in DNA repair, we decided to further explore the 53BP1-dependent pathway. In this study, we uncovered a nuclease, Artemis, as a PTIP-binding protein. Loss of Artemis restores PARPi resistance in BRCA1-deficient cells. Collectively, our data demonstrate that Artemis is the major downstream effector of the 53BP1 pathway, which prevents end resection and promotes nonhomologous end-joining and therefore directly competes with the homologous recombination repair pathway.
Insights
PARP inhibitors are ineffective in BRCA1-deficient cells due to resistance. This study identifies Artemis as a key factor in this resistance, revealing a new therapeutic target for cancer treatment.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- PARP inhibitors (PARPis) are effective against cancers with BRCA1/2 mutations.
- However, resistance to PARPis emerges in cells deficient in both BRCA1 and 53BP1.
- The 53BP1 pathway's role in this resistance is not fully understood.
Purpose of the Study:
- To investigate the downstream effectors of the 53BP1-dependent DNA repair pathway.
- To identify novel targets for overcoming PARPi resistance in BRCA1-deficient cancers.
Main Methods:
- Protein-protein interaction studies to identify PTIP-binding partners.
- CRISPR-Cas9 gene editing to create Artemis-deficient cell lines.
- Assessment of PARPi sensitivity in engineered cell lines.
Main Results:
- Artemis was identified as a PTIP-binding protein, linking it to the 53BP1 pathway.
- Loss of Artemis function restored sensitivity to PARPis in BRCA1-deficient cells.
- Artemis was shown to prevent DNA end resection, favoring nonhomologous end-joining over homologous recombination.
Conclusions:
- Artemis is a critical downstream effector of the 53BP1 pathway.
- Targeting Artemis may represent a strategy to re-sensitize BRCA1-deficient tumors to PARPis.
- Understanding the Artemis-mediated pathway provides insights into DNA repair mechanisms and therapeutic resistance.
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