Specific Low/Endogenous Replication Stress Response Protects Genomic Stability via Controlled ROS Production in an...

Area of Science:

• Cellular biology
• Genomics
• Oxidative stress

Background:

• Cells face daily assaults that threaten genome integrity.
• Replication stress (RS) triggers cellular responses, including canonical DNA damage response (cDDR) and a recently described noncanonical low-level stress-DDR (LoL-DDR).
• LoL-DDR prevents accumulation of 8-oxoguanine, a premutagenic oxidized base, via adaptive reactive oxygen species (ROS) production.

Purpose of the Study:

• To elucidate the mechanisms and regulation of LoL-DDR.
• To investigate the role of LoL-DDR in cancer progression.
• To understand the interplay between ROS, RS, and genome stability.

Main Methods:

• Investigated cellular responses to varying intensities of replication stress.
• Analyzed the production and localization of ROS.
• Examined the roles of DUOX1/DUOX2, NF-κB, PARP1, p53, ATM, and FOXO1 in LoL-DDR.
• Utilized an in vitro cancer progression model.

Main Results:

• LoL-DDR is a diphasic response, distinct from cDDR below a stress threshold.
• RS-induced ROS (RIR) are produced by DUOX1/DUOX2, excluded from the nucleus, and activate FOXO1 detoxification.
• High-intensity RS suppresses RIR via p53 and ATM.
• LoL-DDR is dysregulated in cancer cells, leading to uncontrolled ROS production, 8-oxoguanine accumulation, and a vicious cycle fueling tumorigenesis.
• LoL-DDR dysregulation occurs early in cancer progression.

Conclusions:

• LoL-DDR represents a novel ROS-controlled DNA damage response mechanism.
• The fine-tuning of cellular stress response is critical for maintaining genomic stability.
• Dysregulation of LoL-DDR is a key factor in early cancer development and progression.