Activation-induced cytidine deaminase (AID) catalyses the deamination of 
deoxycytidines to deoxyuracils within immunoglobulin genes to induce somatic 
hypermutation and class-switch recombination1,2. AID-generated deoxyuracils are 
recognized and processed by subverted base-excision and mismatch repair pathways 
that ensure a mutagenic outcome in B cells3-6. However, why these DNA repair 
pathways do not accurately repair AID-induced lesions remains unknown. Here, 
using a genome-wide CRISPR screen, we show that FAM72A is a major determinant 
for the error-prone processing of deoxyuracils. 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, and reduced genome-wide deoxyuracils. The somatic hypermutation spectrum 
in B cells from Fam72a-/- mice is opposite to that observed in mice deficient in 
uracil DNA glycosylase 2 (UNG2)7, which suggests that UNG2 is hyperactive in 
FAM72A-deficient cells. Indeed, FAM72A binds to UNG2, resulting in reduced 
levels of UNG2 protein in the G1 phase of the cell cycle, coinciding with peak 
AID activity. FAM72A therefore causes U·G mispairs to persist into S phase, 
leading to error-prone processing by mismatch repair. By disabling the DNA 
repair pathways that normally efficiently remove deoxyuracils from DNA, FAM72A 
enables AID to exert its full effects on antibody maturation. This work has 
implications in cancer, as the overexpression of FAM72A that is observed in many 
cancers8 could promote mutagenesis.