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Fam72a Antagonizes Ung2 to Promote Mutagenic Repair During Antibody Maturation Publisher Pubmed



Feng Y1 ; Li C1, 13 ; Stewart JA2 ; Barbulescu P1 ; Desivo NS3, 4 ; Alvarezquilon A5, 6 ; Pezo RC7, 8 ; Perera MLW2 ; Chan K9 ; Tong AHY9 ; Mohamadramshan R2 ; Berru M1 ; Nakib D1 ; Li G1 Show All Authors
Authors
  1. Feng Y1
  2. Li C1, 13
  3. Stewart JA2
  4. Barbulescu P1
  5. Desivo NS3, 4
  6. Alvarezquilon A5, 6
  7. Pezo RC7, 8
  8. Perera MLW2
  9. Chan K9
  10. Tong AHY9
  11. Mohamadramshan R2
  12. Berru M1
  13. Nakib D1
  14. Li G1
  15. Kardar GA10
  16. Carlyle JR1
  17. Moffat J5, 9, 11
  18. Durocher D5, 6
  19. Di Noia JM3, 4
  20. Bhagwat AS2, 12
  21. Martin A1
Show Affiliations
Authors Affiliations
  1. 1. Department of Immunology, University of Toronto, Toronto, ON, Canada
  2. 2. Department of Chemistry, Wayne State University, Detroit, MI, United States
  3. 3. Institut de recherches cliniques de Montreal, Montreal, QC, Canada
  4. 4. Molecular Biology Programs, Department of Medicine, University of Montreal, Montreal, QC, Canada
  5. 5. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
  6. 6. Lunenfeld–Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
  7. 7. Sunnybrook Health Sciences Center, Toronto, ON, Canada
  8. 8. Department of Medicine, University of Toronto, Toronto, ON, Canada
  9. 9. Donnelly Centre, University of Toronto, Toronto, ON, Canada
  10. 10. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
  11. 11. Institute for Biomedical Engineering, University of Toronto, Toronto, ON, Canada
  12. 12. Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, United States
  13. 13. School of Medicine, The Chinese University of Hong Kong, Shenzhen, China

Source: Nature Published:2021


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