The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation.
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.
Zan
H
H
Division of Molecular Immunology, Department of Pathology, Cornell University Weill Medical College, New York, NY 10021, USA.
Komori
A
A
Li
Z
Z
Cerutti
A
A
Schaffer
A
A
Flajnik
M F
MF
Diaz
M
M
Casali
P
P
D001402:B-Lymphocytes; D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007136:Immunoglobulins / Q000235:genetics*; D016296:Mutagenesis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D000099270:Y-Family DNA Polymerases
D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D007136:Immunoglobulins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; C425929:DNA polymerase zeta; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases