Fam72a enforces error-prone DNA repair during antibody diversification.

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. © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Mélanie Rogier, Jacques Moritz, Isabelle Robert, Chloé Lescale, Vincent Heyer, Arthur Abello, Ophélie Martin, Katia Capitani, Morgane Thomas, Anne-Sophie Thomas-Claudepierre, Brice Laffleur, Florence Jouan, Eric Pinaud, Karin Tarte, Michel Cogné, Silvestro G Conticello, Evi Soutoglou, Ludovic Deriano, Bernardo Reina-San-Martin. Fam72a enforces error-prone DNA repair during antibody diversification. Nature. 2021 Dec;600(7888):329-333

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PMID: 34819671

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