REV7 is required for processing AID initiated DNA lesions in activated B cells

Nat Commun. 2020 Jun 4;11(1):2812. doi: 10.1038/s41467-020-16632-8.

Abstract

Activation-induced cytidine deaminase (AID) initiates both antibody class switch recombination (CSR) and somatic hypermutation (SHM) in antibody diversification. DNA double-strand break response (DSBR) factors promote rearrangement in CSR, while translesion synthesis (TLS) polymerases generate mutations in SHM. REV7, a component of TLS polymerase zeta, is also a downstream effector of 53BP1-RIF1 DSBR pathway. Here, we study the multi-functions of REV7 and find that REV7 is required for the B cell survival upon AID-deamination, which is independent of its roles in DSBR, G2/M transition or REV1-mediated TLS. The cell death in REV7-deficient activated B cells can be fully rescued by AID-deficiency in vivo. We further identify that REV7-depedent TLS across UNG-processed apurinic/apyrimidinic sites is required for cell survival upon AID/APOBEC deamination. This study dissects the multiple roles of Rev7 in antibody diversification, and discovers that TLS is not only required for sequence diversification but also B cell survival upon AID-initiated lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Cell Survival
  • Cytidine Deaminase / metabolism*
  • DNA Breaks, Double-Stranded*
  • DNA Mutational Analysis
  • DNA-Binding Proteins / metabolism
  • DNA-Directed DNA Polymerase / metabolism
  • Female
  • Genotype
  • Immunoglobulin Class Switching
  • Lymphocyte Activation*
  • Mad2 Proteins / metabolism*
  • Male
  • Mice
  • Mutation*
  • Recombination, Genetic
  • Somatic Hypermutation, Immunoglobulin
  • Uracil-DNA Glycosidase / genetics

Substances

  • DNA-Binding Proteins
  • Mad2 Proteins
  • Mad2l2 protein, mouse
  • DNA-Directed DNA Polymerase
  • REV3L protein, mouse
  • Uracil-DNA Glycosidase
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase