Restriction of AID activity and somatic hypermutation by PARP-1

Nucleic Acids Res. 2019 Aug 22;47(14):7418-7429. doi: 10.1093/nar/gkz466.

Abstract

Affinity maturation of the humoral immune response depends on somatic hypermutation (SHM) of immunoglobulin (Ig) genes, which is initiated by targeted lesion introduction by activation-induced deaminase (AID), followed by error-prone DNA repair. Stringent regulation of this process is essential to prevent genetic instability, but no negative feedback control has been identified to date. Here we show that poly(ADP-ribose) polymerase-1 (PARP-1) is a key factor restricting AID activity during somatic hypermutation. Poly(ADP-ribose) (PAR) chains formed at DNA breaks trigger AID-PAR association, thus preventing excessive DNA damage induction at sites of AID action. Accordingly, AID activity and somatic hypermutation at the Ig variable region is decreased by PARP-1 activity. In addition, PARP-1 regulates DNA lesion processing by affecting strand biased A:T mutagenesis. Our study establishes a novel function of the ancestral genome maintenance factor PARP-1 as a critical local feedback regulator of both AID activity and DNA repair during Ig gene diversification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • DNA Damage
  • DNA Repair
  • Genes, Immunoglobulin / genetics*
  • Humans
  • Immunoglobulin Variable Region / genetics*
  • Mice
  • Mutation
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Somatic Hypermutation, Immunoglobulin / genetics*

Substances

  • Immunoglobulin Variable Region
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase