RAD9 deficiency enhances radiation induced bystander DNA damage and transcriptomal response

Area of Science:

• Cellular and Molecular Biology
• Radiation Biology
• Genetics

Background:

• Radiation-induced bystander effects are critical for understanding cellular responses to irradiation and associated human health risks.
• Intra-cellular and inter-cellular signaling pathways propagate bystander responses, but their precise mechanisms remain incompletely defined.

Purpose of the Study:

• To investigate the role of RAD9 in mediating radiation-induced bystander effects.
• To analyze the impact of RAD9 deficiency on chromosomal damage and gene expression in bystander cells.

Main Methods:

• Assessed bystander responses in Mrad9+/+ and Mrad9-/- mouse embryonic stem cells and human H1299 cells with varying RAD9 levels after 1 Gy alpha particle exposure.
• Quantified chromosomal aberrations and micronuclei formation.
• Utilized microarray analysis to profile transcriptomes of directly irradiated and bystander cells.

Main Results:

• Mrad9 null status enhanced radiation-induced chromatid aberrations in bystander mouse cells.
• Reduced RAD9 levels in human cells led to a higher frequency of radiation-induced bystander micronuclei formation.
• RAD9 reduction altered stress response pathways and affected MAPK signaling, with predicted differential activation of SP1 and NUPR1 transcriptional regulators.

Conclusions:

• RAD9 plays a significant role in modulating radiation-induced bystander effects.
• RAD9 deficiency enhances cellular sensitivity to radiation-induced bystander signaling.
• Hypoxia-induced factor 1 alpha (HIF1α) activation in irradiated cells may negatively predict bystander responses.