Fam72a controls the balance between error-prone and error-free DNA repair during antibody diversification

Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA repair. B cell receptor diversification through somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by cytidine deamination in DNA mediated by activation induced cytidine deaminase (AID)[1][1] and by the subsequent excision of the resulting uracils by Uracil DNA glycosylase (UNG) and by mismatch repair (MMR) proteins[2][2]–[4][3]. Although uracils arising in DNA are faithfully repaired[2][2]–[7][4], it is not known how these pathways are co-opted to generate mutations and double stranded DNA breaks (DSBs) in the context of SHM and CSR[2][2],[4][3],[8][5]. Here we have performed a genome-wide CRISPR/Cas9 knockout screen for genes involved in CSR. The screen identified FAM72A, a protein that interacts with the nuclear isoform of UNG (UNG2)[9][6] and that is overexpressed in several cancers[9][6]. We show that the FAM72A-UNG2 interaction controls the protein levels of UNG2 and that CSR is defective in Fam72a−/− B cells due to the specific upregulation of UNG2. Moreover, we show that in Fam72a−/− B cells SHM is reduced by 5-fold and that upregulation of UNG2 results in a skewed mutation pattern. Our results are consistent with a model in which FAM72A interacts with UNG2 to control its physiological level by triggering its degradation. Consequently, deficiency in Fam72a leads to supraphysiological levels of UNG2 and enhanced uracil excision, shifting the balance from error-prone to error-free DNA repair. Our findings have potential implications for tumorigenesis, as Fam72a overexpression would lead to reduced UNG2 levels, shifting the balance toward mutagenic DNA repair and rendering cells more prone to acquire mutations. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-4 [4]: #ref-7 [5]: #ref-8 [6]: #ref-9