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Updated: Apr 26, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells
Philip W Noble1, Melissa R Young1, Sasha Bernatsky2
1From the Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520.
Abstract:
Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might have potential as therapeutic agents targeted towards DNA repair-deficient malignancies. We identified the lupus autoantibody 5C6 as a cell-penetrating nucleolytic antibody and found that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. 5C6 selectively induced γH2AX in, and suppressed the growth of, the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus.
Insights
Lupus autoantibodies can target cancer cells. The antibody 5C6 selectively damages DNA repair-deficient cancer cells, showing potential for targeted cancer therapy and explaining lower cancer risk in lupus patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Cancer cells with DNA repair defects are vulnerable to DNA-damaging agents.
- Delivering therapeutics to cancer cell nuclei is a significant challenge.
- Certain lupus autoantibodies possess nucleolytic activity and can penetrate cell nuclei.
Purpose of the Study:
- To investigate the potential of lupus autoantibodies as targeted therapeutic agents for DNA repair-deficient malignancies.
- To identify and characterize cell-penetrating, nucleolytic lupus autoantibodies for cancer therapy.
- To explore the therapeutic efficacy of the lupus autoantibody 5C6 against cancer cells.
Main Methods:
- Identification of the lupus autoantibody 5C6 as a cell-penetrating, nucleolytic antibody.
- Utilizing a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells.
- Assessing the selective induction of γH2AX and growth suppression in BRCA2-deficient cells.
Main Results:
- The lupus autoantibody 5C6 demonstrated cell-penetrating and nucleolytic properties.
- 5C6 selectively induced γH2AX, a DNA damage marker, in BRCA2-deficient DLD1 colon cancer cells.
- 5C6 significantly suppressed the growth of BRCA2-deficient cancer cells.
Conclusions:
- The lupus autoantibody 5C6 shows potential for targeted therapy in DNA repair-deficient cancers.
- Further studies on lupus autoantibodies may identify novel therapeutic candidates for cancer treatment.
- The findings support the hypothesis that lupus autoantibodies may contribute to reduced cancer risk in systemic lupus erythematosus.
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