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Updated: Dec 29, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability
Katerina D Fagan-Solis1, Dennis A Simpson1, Rashmi J Kumar1
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Abstract:
The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation.
Insights
The Mre11-Rad50-Nbs1 complex suppresses cancer growth by sensing DNA damage independently of p53. Its dysfunction drives tumor instability and sensitivity to specific therapies in breast cancer.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The Mre11-Rad50-Nbs1 complex acts as a DNA double-strand break sensor, initiating a tumor-suppressive DNA damage response (DDR) under oncogenic stress.
- The precise mechanisms by which this complex exerts its tumor-suppressive functions remain largely unelucidated.
Purpose of the Study:
- To investigate the role of the Mre11 complex in suppressing oncogene-induced proliferation and DNA damage.
- To explore the consequences of Mre11 complex dysfunction in breast tumorigenesis and its therapeutic implications.
Main Methods:
- Utilized a genetically inducible primary mammary epithelial cell model.
- Created breast tumorigenesis models with a hypomorphic Mre11 allele.
- Analyzed DNA damage, R-loop accumulation, chromosomal instability, and copy number alterations.
- Examined Mre11 complex dysfunction in human triple-negative breast cancers.
Main Results:
- Mre11 suppresses proliferation and DNA damage induced by oncogenic drivers via a p53-independent pathway.
- Mre11 deficiency leads to increased oncogene-induced DNA damage, R-loop accumulation, and copy number loss-associated chromosomal instability.
- Mre11 complex dysfunction correlates with heightened sensitivity to DNA-damaging agents, ATR inhibitors, and PARP inhibitors in triple-negative breast cancers.
Conclusions:
- Deficiencies in the Mre11-dependent DDR promote proliferation and genome instability in p53-deficient breast cancers.
- Mre11 complex dysfunction presents a potential therapeutic target for specific breast cancer subtypes.
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