Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Noncoding RNAs are crucial for biological processes and are regulated by cellular RNA surveillance.
• The RNA exosome, a key 3' RNA exoribonuclease, comprises nine core and two catalytic subunits.
• DIS3 is a catalytic subunit of the RNA exosome involved in RNA processing.

Purpose of the Study:

• To investigate the role of the RNA exosome catalytic subunit DIS3 in B cell biology.
• To understand how DIS3 deficiency affects the immunoglobulin heavy chain (Igh) locus.
• To explore the impact of DIS3 on genome organization and DNA repair.

Main Methods:

• Development of a conditional mouse model for DIS3 deficiency in B cells.
• Analysis of Igh locus integrity, CTCF binding, and cohesin localization.
• Assessment of DNA repair pathways, including somatic hypermutation and end-joining repair.

Main Results:

• DIS3-deficient B cells exhibit altered Igh locus architecture, with accumulated DNA-associated RNAs and disorganized CTCF and cohesin.
• Activation-induced cytidine deaminase-mediated nicks increase, affecting somatic hypermutation and promoting microhomology-mediated end-joining repair.
• DIS3 deficiency leads to reduced class-switch recombination but increased chromosomal translocations in B cells.

Conclusions:

• DIS3 plays a critical role in maintaining Igh locus architecture and regulating DNA repair pathways in B cells.
• DIS3-mediated noncoding RNA processing is essential for controlling genome organization.
• Dysregulation of DIS3 contributes to genomic instability and potentially oncogenesis.