Fam72a enforces error-prone DNA repair during antibody diversification

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Humoral immune responses depend on DNA damage, mutagenesis, and error-prone DNA repair.
• B cell receptor diversification involves somatic hypermutation and class-switch recombination, initiated by activation-induced cytidine deaminase (AID).
• The precise mechanisms by which DNA repair pathways generate mutations and DNA breaks during these processes are not fully understood.

Purpose of the Study:

• To identify novel genes involved in class-switch recombination.
• To elucidate the role of FAM72A in DNA repair and B cell diversification.
• To understand the implications of FAM72A-mediated regulation for tumorigenesis.

Main Methods:

• Genome-wide CRISPR-Cas9 knockout screen for class-switch recombination genes.
• Analysis of B cells from Fam72a knockout mice.
• Biochemical assays to study FAM72A-UNG2 interaction and uracil excision.

Main Results:

• FAM72A was identified as a key protein interacting with uracil DNA glycosylase 2 (UNG2).
• Class-switch recombination and somatic hypermutation were defective in Fam72a knockout B cells due to altered UNG2 levels.
• FAM72A regulates UNG2 degradation, influencing the balance between error-prone and error-free DNA repair.

Conclusions:

• FAM72A controls the physiological levels of UNG2, thereby regulating uracil excision and DNA repair pathways.
• Dysregulation of FAM72A-UNG2 interaction can shift DNA repair towards mutagenic processes, potentially contributing to cancer.
• Findings provide insights into the molecular mechanisms of B cell diversification and have implications for cancer research.