TY - JOUR
T1 - The translesion DNA polymerase ζ plays a major role in Ig and bcl-6 somatic hypermutation
AU - Zan, Hong
AU - Komori, Atsumasa
AU - Li, Zongdong
AU - Cerutti, Andrea
AU - Schaffer, András
AU - Flajnik, Martin F.
AU - Diaz, Marilyn
AU - Casali, Paolo
N1 - Funding Information:
We are grateful to Dr. William K. Holloman for helpful discussions and to Dr. Michael M. Seidman for the shuttle vector pSP189 and the test E. Coli strain MBM7070. We thank Shefali Shah and Pat Dramitinos for their excellent technical assistance. This work was supported by the National Institutes of Health grants AR 40908, AG 13910, and AI 45011 and by a Research Grant from the SLE Foundation, Inc. (New York) (to P.C.). A.S. was supported by a Cancer Research Institute (New York) fellowship.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
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U2 - 10.1016/S1074-7613(01)00142-X
DO - 10.1016/S1074-7613(01)00142-X
M3 - Article
C2 - 11371365
AN - SCOPUS:0035005241
VL - 14
SP - 643
EP - 653
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 5
ER -