Tumors lacking the BRCA1 and BRCA2 (BRCA) hereditary breast cancer genes display heightened sensitivity to anti-cancer treatments, such as inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). However, when resistance develops, treatments are lacking. Using CRISPR technology, we discovered that enhancing homologous recombination through increased DNA end resection in BRCA1-deficient cells by loss of the 53BP1-Shieldin complex-which is associated with resistance to PARP inhibitors-also heightens sensitivity to DNA nicks. The sensitivity is caused by hyper-resection of nicks into extensive single-stranded regions that trigger cell death. Based on these findings and that nicks limit tumor formation in mice, we propose nickases as a tool for personalized medicine. Moreover, our findings indicate that restricting nick expansion is a critical function of the 53BP1-Shieldin complex.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s43018-024-00902-1 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability.
Nat Cancer
January 2025
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Tumors lacking the BRCA1 and BRCA2 (BRCA) hereditary breast cancer genes display heightened sensitivity to anti-cancer treatments, such as inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). However, when resistance develops, treatments are lacking. Using CRISPR technology, we discovered that enhancing homologous recombination through increased DNA end resection in BRCA1-deficient cells by loss of the 53BP1-Shieldin complex-which is associated with resistance to PARP inhibitors-also heightens sensitivity to DNA nicks.
View Article and Find Full Text PDFDocetaxel response in BRCA1,p53-deficient mammary tumor cells is affected by Huntingtin and BAP1.
Proc Natl Acad Sci U S A
December 2024
Department of Infectious Diseases and Pathobiology, Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
Taxanes are frequently used anticancer drugs known to kill tumor cells by inducing mitotic aberrations and segregation defects. A defining feature of specific cancers, notably triple-negative breast cancer (TNBC) and particularly those deficient in BRCA1, is chromosomal instability (CIN). Here, we focused on understanding the mechanisms of docetaxel-induced cytotoxicity, especially in the context of BRCA1-deficient TNBC.
View Article and Find Full Text PDFImpact of Optimized Ku-DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response.
Cancers (Basel)
September 2024
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Article Synopsis
- DNA-dependent protein kinase (DNA-PK) plays a crucial role in repairing DNA double-strand breaks and is a target for cancer therapies to enhance the effectiveness of radiation treatments.
- Researchers have developed new oxindole Ku-DNA binding inhibitors (Ku-DBis) that show better cellular uptake and strong inhibition of Ku proteins, demonstrating variable effectiveness across different non-small cell lung cancer (NSCLC) cell lines.
- In vivo studies reveal that Ku-DBis can block DNA-PK autophosphorylation, alter DNA damage responses, and lower tumor cell growth, indicating their potential use in improving cancer treatment outcomes.
Direct DNA binding by BRCA1 on β-hCG promoter and its clinical implications.
Heliyon
September 2024
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
Article Synopsis
- The study investigates the role of β-hCG in breast cancer, particularly in Breast Invasive Carcinoma (BRCA), assessing its gene expression and implications for clinical outcomes.
- Data from various gene expression databases and laboratory techniques were used to analyze β-hCG levels, particularly focusing on its connection to BRCA1 mutations and immune cell presence in tumors.
- Results indicate that β-hCG is upregulated in breast cancers with BRCA1 mutations, suggesting it could serve as a potential target for treatment in BRCA1-deficient patients.
Targeting GPX4-mediated ferroptosis protection sensitizes BRCA1-deficient cancer cells to PARP inhibitors.
Redox Biol
October 2024
School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address:
Article Synopsis
- BRCA1 is a critical tumor suppressor gene often mutated in ovarian and breast cancers, leading to issues in DNA repair and increased genomic instability, which can be targeted by PARP inhibitors (PARPi).
- This study reveals that BRCA1 enhances susceptibility to ferroptosis (a type of regulated cell death) by promoting the degradation of the protein GPX4, which protects cells from oxidative damage.
- The research shows that blocking GPX4 can boost the effectiveness of PARPi treatment in BRCA1-deficient ovarian cancer cells, suggesting that targeting GPX4 could be a promising therapeutic strategy for treating these cancers.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!