DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The mechanism of somatic hypermutation (SMH) in diversifying rearranged immunoglobulin (Ig) genes remains unclear.
• Germinal centers (GCs) are key sites for B cell maturation and antibody diversification.

Purpose of the Study:

• To investigate the role of DNA double-strand breaks (DSBs) in the process of somatic hypermutation.
• To identify the specific locations and characteristics of DSBs within Ig genes during B cell diversification.

Main Methods:

• Utilized VDJ passenger Ig heavy chain (IgH) knockin mouse models.
• Analyzed DNA double-strand breaks (DSBs) in germinal center (GC) B cells.
• Examined the distribution of DSBs in relation to mutation patterns and DNA motifs.

Main Results:

• A high frequency of DSBs was observed in the targeted VDJ passenger Ig gene of GC B cells.
• DSBs distribution paralleled mutation patterns within the hypermutation domain.
• DSBs preferentially occurred at RGYW motifs, known hotspots for SMH.
• DSB introduction was dependent on transcriptional activity.

Conclusions:

• Secondary diversification of rearranged V gene segments is linked to an error-prone nonhomologous DSB repair system.
• This repair system operates within B cells in the germinal center.
• DSBs are a critical component in the somatic hypermutation process for immunoglobulin gene diversification.