The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation

Immunity. 2001 May;14(5):643-53. doi: 10.1016/s1074-7613(01)00142-x.


Ig somatic mutations would be introduced by a polymerase (pol) while repairing DNA outside main DNA replication. We show that human B cells constitutively express the translesion pol zeta, which effectively extends DNA past mismatched bases (mispair extender), and pol eta, which bypasses DNA lesions in an error-free fashion. Upon B cell receptor (BCR) engagement and coculture with activated CD4+ T cells, these lymphocytes upregulated pol zeta, downregulated pol eta, and mutated the Ig and bcl-6 genes. Inhibition of the pol zeta REV3 catalytic subunit by specific phosphorothioate-modified oligonucleotides impaired Ig and bcl-6 hypermutation and UV damage-induced DNA mutagenesis, without affecting cell cycle or viability. Thus, pol zeta plays a critical role in Ig and bcl-6 hypermutation, perhaps facilitated by the downregulation of pol eta.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • B-Lymphocytes
  • Cell Line
  • DNA Damage
  • DNA-Binding Proteins / genetics*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / physiology*
  • Down-Regulation
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Joining Region / genetics
  • Immunoglobulin Variable Region / genetics
  • Immunoglobulins / genetics*
  • Mutagenesis*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-bcl-6
  • Time Factors
  • Transcription Factors / genetics*
  • Up-Regulation


  • DNA-Binding Proteins
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Joining Region
  • Immunoglobulin Variable Region
  • Immunoglobulins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Transcription Factors
  • DNA polymerase zeta
  • DNA-Directed DNA Polymerase
  • Rad30 protein