Fam72a, a poorly characterized yet evolutionarily conserved gene across multicellular organisms, plays multifaceted roles. It is involved in cell-cycle regulation, as it is transcriptionally and post-transcriptionally regulated by FoxM1 and APC/C respectively. Functionally, it binds to tubulin and subunits of PP2A-B56 to modulate phosphorylation, thus affecting cell-cycle progression and apoptosis signaling [2]. Additionally, it is crucial in antibody maturation, influencing error-prone DNA repair pathways [1,3,4].

In antibody-related processes, Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a-/-mice exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, along with reduced genome-wide deoxyuracils [1]. The somatic hypermutation spectrum in B cells from Fam72a-/-mice is opposite to that in UNG2-deficient mice, suggesting hyperactive UNG2 in FAM72A-deficient cells. FAM72A binds to UNG2, reducing UNG2 protein levels in the G1 phase, causing U·G mispairs to persist into S phase and leading to error-prone processing by mismatch repair [1,3]. It also recruits a CTLH E3 ligase complex to target UNG2 for proteasomal degradation, and deficiency in CTLH complex components results in elevated UNG2 and reduced SHM and CSR [4].

In summary, Fam72a functions as a cell-cycle-controlled gene during proliferation, antagonizes apoptosis, and is crucial for error-prone DNA repair during antibody maturation. The study of Fam72a-/-mice has significantly advanced our understanding of its role in antibody diversification and has potential implications for tumorigenesis, as its overexpression in many cancers could promote mutagenesis [1,2,3,4].