FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation

Yuqing Feng, Conglei Li, Jessica A. Stewart, Philip Barbulescu, Noé Seija Desivo, Alejandro Álvarez-Quilón, Rossanna C. Pezo, Madusha L. W. Perera, Katherine Chan, Amy Hin Yan Tong, Rukshana Mohamad-Ramshan, Maribel Berru, Diana Nakib, Gavin Li, Gholam Ali Kardar, James R. Carlyle, Jason Moffat, Daniel Durocher, Javier M. Noia, Ashok S. Bhagwat and Alberto Martin ()
Additional contact information
Yuqing Feng: University of Toronto
Conglei Li: University of Toronto
Jessica A. Stewart: Wayne State University
Philip Barbulescu: University of Toronto
Noé Seija Desivo: Institut de recherches cliniques de Montréal
Alejandro Álvarez-Quilón: University of Toronto
Rossanna C. Pezo: Sunnybrook Health Sciences Center
Madusha L. W. Perera: Wayne State University
Katherine Chan: University of Toronto
Amy Hin Yan Tong: University of Toronto
Rukshana Mohamad-Ramshan: Wayne State University
Maribel Berru: University of Toronto
Diana Nakib: University of Toronto
Gavin Li: University of Toronto
Gholam Ali Kardar: Tehran University of Medical Sciences
James R. Carlyle: University of Toronto
Jason Moffat: University of Toronto
Daniel Durocher: University of Toronto
Javier M. Noia: Institut de recherches cliniques de Montréal
Ashok S. Bhagwat: Wayne State University
Alberto Martin: University of Toronto

Nature, 2021, vol. 600, issue 7888, 324-328

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-04144-4

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