The DNA Damage Response Regulates RAG1/2 Expression in Pre-B Cells through ATM-FOXO1 Signaling

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Recombination activating gene (RAG) 1 and RAG2 initiate V(D)J recombination in lymphocytes.
• Dysregulated RAG1/2 expression risks DNA damage and aberrant recombination.
• Ataxia telangiectasia mutated (ATM) kinase repairs RAG1/2-induced DNA breaks.

Purpose of the Study:

• To investigate the impact of genotoxic stress on RAG1/2 expression in pre-B cells.
• To elucidate the role of ATM and FOXO1 in this regulatory pathway.

Main Methods:

• Assessed RAG1/2 expression under genotoxic stress in pre-B cells.
• Investigated ATM-dependent regulation of RAG1/2 mRNA and protein.
• Analyzed FOXO1 binding to the RAG1/2 enhancer (Erag) and FOXO1 cleavage.

Main Results:

• Genotoxic stress triggers rapid, ATM-dependent downregulation of RAG1/2 expression.
• DNA damage causes loss of FOXO1 binding to Erag and FOXO1 cleavage.
• RAG1/2 activity-induced DNA damage downmodulates RAG1/2 expression, indicating negative feedback.

Conclusions:

• Pre-B cells possess a protective mechanism against DNA damage-induced aberrant recombination.
• This involves ATM-dependent regulation of FOXO1 binding to the Erag enhancer region.
• This mechanism mitigates risks of chromosomal translocations during genotoxic stress.