The Translesion DNA Polymerase ζ Plays a Major Role in Ig and bcl-6 Somatic Hypermutation

• Published in: Immunity (Cambridge, Mass.) Vol. 14; no. 5; pp. 643 - 653
• Main Authors: Zan, Hong, Komori, Atsumasa, Li, Zongdong, Cerutti, Andrea, Schaffer, András, Flajnik, Martin F., Diaz, Marilyn, Casali, Paolo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2001
• Subjects: B-Lymphocytes; bcl-6 gene; 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; oligonucleotides; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-6; Time Factors; Transcription Factors - genetics; Up-Regulation
• ISSN: 1074-7613; 1097-4180
• 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 ζ, which effectively extends DNA past mismatched bases (mispair extender), and pol η, 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 ζ, downregulated pol η, and mutated the Ig and bcl-6 genes. Inhibition of the pol ζ 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 ζ plays a critical role in Ig and bcl-6 hypermutation, perhaps facilitated by the downregulation of pol η.