Our immune system protects us from infection by producing antibodies. To respond to countless pathogens we may encounter in everyday life, B cells deliberately introduce small bursts of mutations in their antibody genes, a process that increases antibody diversity and improves immune protection. While this mutational process is essential for immunity, it carries risks, as the same mechanism that generates beneficial mutations can create harmful DNA damage that leads to genomic instability and B cell lymphoma.
The mutations within the B cell genome are initiated by activation-induced cytidine deaminase (AID), which converts DNA bases into lesions that can be repaired in either an error-free or mutagenic manner. Why B cells intentionally bias this DNA repair process toward mutagenesis has been a puzzling phenomenon for decades. We recently identified FAM72A as a key regulator of this process. Mechanistically, FAM72A promotes the degradation of the base excision repair enzyme UNG2, thereby limiting error-free repair and preserving AID-induced lesions for further mutagenic processing. Importantly, FAM72A is aberrantly upregulated in multiple cancers and its overexpression is associated with high tumor mutation burden and immune evasion in patients, suggesting it has potential tumorigenic role during AID-induced B cell lymphomagenesis.
The major focus of my group is to use molecular and immunological approaches to investigate how FAM72A is regulated to support its physiological role in antibody gene diversification while preventing it from exacerbating AID-induced off-target mutagenesis. This work aligns with my broader research program on studying context-dependent effects of mutagenesis, and especially how mutations can be harnessed to benefit immunity, yet become harmful in disease settings such as B cell lymphoma.