LSD1 mediated changes in the local redox environment during the DNA damage response

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Cellular redox state is crucial and influenced by various conditions.
• Reactive oxygen species (ROS) play a significant role in cellular signaling and damage.
• DNA damage response pathways are essential for maintaining genomic integrity.

Purpose of the Study:

• To investigate the role of the chromatin remodeling factor and monoamine oxidase LSD1/KDM1A in generating reactive oxygen species (ROS) upon DNA damage.
• To determine if localized hydrogen peroxide (H2O2) generated by LSD1 affects DNA repair protein function.
• To explore the impact of cellular redox state on DNA double-strand break (DSB) repair pathway choice.

Main Methods:

• Exposure of cells to low levels of ectopic hydrogen peroxide (H2O2).
• Induction of DNA double-strand breaks (DSBs) using laser light.
• Determination of recruitment kinetics of non-homologous end joining (NHEJ) protein Ku80 and homologous recombination (HR) protein Nbs1 to DNA damage sites.

Main Results:

• Pretreatment with H2O2 significantly decreased the recruitment of Ku80 to DNA damage sites.
• Pretreatment with H2O2 significantly increased the recruitment of HR end-binding protein Nbs1 to DNA damage sites.
• LSD1/KDM1A was identified as a source of ROS generation in response to DNA damage.

Conclusions:

• The cellular redox state, influenced by ROS generated by LSD1, can modulate the choice between DNA repair pathways (NHEJ and HR).
• This modulation has implications for the efficacy of chemotherapeutic strategies targeting cancer cells, as effectiveness may depend on the cell's redox state and predominant DNA repair pathway.
• Understanding the interplay between redox state and DNA repair is critical for optimizing cancer treatment approaches.