Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA 
repair. Diversification of B cell receptors through somatic hypermutation and 
class-switch recombination are initiated by cytidine deamination in DNA mediated 
by activation-induced cytidine deaminase (AID)1 and by the subsequent excision 
of the resulting uracils by uracil DNA glycosylase (UNG) and by mismatch repair 
proteins1-3. Although uracils arising in DNA are accurately repaired1-4, how 
these pathways are co-opted to generate mutations and double-strand DNA breaks 
in the context of somatic hypermutation and class-switch recombination is 
unknown1-3. Here we performed a genome-wide CRISPR-Cas9 knockout screen for 
genes involved in class-switch recombination and identified FAM72A, a protein 
that interacts with the nuclear isoform of UNG (UNG2)5 and is overexpressed in 
several cancers5. We show that the FAM72A-UNG2 interaction controls the levels 
of UNG2 and that class-switch recombination is defective in Fam72a-/- B cells 
due to the upregulation of UNG2. Moreover, we show that somatic hypermutation is 
reduced in Fam72a-/- B cells and that its pattern is skewed upon upregulation of 
UNG2. Our results are consistent with a model in which FAM72A interacts with 
UNG2 to control its physiological level by triggering its degradation, 
regulating the level of uracil excision and thus the balance between error-prone 
and error-free DNA repair. Our findings have potential implications for 
tumorigenesis, as reduced levels of UNG2 mediated by overexpression of Fam72a 
would shift the balance towards mutagenic DNA repair, rendering cells more prone 
to acquire mutations.