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Oncogene-triggered suppression of DNA repair leads to DNA instability in cancer
Julia A Yaglom1, Christopher McFarland2, Leonid Mirny3
1Department Biochemistry, Boston University School of Medicine, Boston, MA.
Abstract:
DNA instability is an important contributor to cancer development. Previously, defects in the chromosome segregation and excessive DNA double strand breaks due to the replication or oxidative stresses were implicated in DNA instability in cancer. Here, we demonstrate that DNA instability can directly result from the oncogene-induced senescence signaling. Expression of the activated form of Her2 oncogene, NeuT, in immortalized breast epithelial cells led to downregulation of the major DNA repair factor histone H2AX and a number of other components of the HR and NHEJ double strand DNA breaks repair pathways. H2AX expression was regulated at the transcriptional level via a senescence pathway involving p21-mediated regulation of CDK and Rb1. The p21-dependent downregulation of H2AX was seen both in cell culture and the MMTV-neu mouse model of Her2-positive breast cancer. Importantly, downregulation of H2AX upon Her2/NeuT expression impaired repair of double strand DNA breaks. This impairment resulted in both increased DNA instability in the form of somatic copy number alterations, and in increased sensitivity to the chemotherapeutic drug doxorubicin. Overall, these findings indicate that the Her2/NeuT oncogene signaling directly potentiates DNA instability and increases sensitivity to DNA damaging treatments.
Insights
Oncogene signaling, like Her2/NeuT, can cause DNA instability by reducing DNA repair protein H2AX. This increases cancer development and sensitivity to chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA instability is a key factor in cancer development.
- Previous research linked chromosome segregation defects and DNA double-strand breaks to genomic instability.
- The role of oncogene-induced senescence in DNA instability was less understood.
Purpose of the Study:
- To investigate if oncogene-induced senescence signaling directly causes DNA instability.
- To explore the molecular mechanisms linking Her2/NeuT oncogene activation to DNA repair.
- To assess the impact of this pathway on cancer progression and treatment sensitivity.
Main Methods:
- Utilized immortalized breast epithelial cells expressing the activated Her2 oncogene (NeuT).
- Analyzed the expression of DNA repair factors, including histone H2AX, and components of homologous recombination (HR) and non-homologous end joining (NHEJ) pathways.
- Investigated the transcriptional regulation of H2AX via senescence pathways involving p21, CDK, and Rb1.
- Studied the MMTV-neu mouse model for Her2-positive breast cancer.
- Assessed DNA repair efficiency, DNA instability (somatic copy number alterations), and sensitivity to doxorubicin.
Main Results:
- Her2/NeuT oncogene expression led to the downregulation of histone H2AX and other DNA double-strand break repair pathway components.
- H2AX downregulation was transcriptionally regulated through a senescence pathway involving p21, CDK, and Rb1.
- This downregulation impaired the repair of double-strand DNA breaks.
- Impaired repair resulted in increased DNA instability and heightened sensitivity to doxorubicin.
Conclusions:
- Oncogene-induced senescence signaling, specifically via Her2/NeuT, directly potentiates DNA instability.
- The downregulation of H2AX is a key mechanism by which Her2/NeuT signaling promotes genomic instability.
- These findings highlight a direct link between oncogene activation, impaired DNA repair, and increased susceptibility to DNA damaging agents in cancer.
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