Absence of DNA polymerase theta results in decreased somatic hypermutation frequency and altered mutation patterns in Ig

作者：Masuda Keiji; Ouchida Rika; Hikida Masaki; Nakayama Manabu; Ohara Osamu; Kurosaki Tomohiro; O Wang Jiyanq^*

来源：DNA Repair, 2006, 5(11): 1384-1391.

DOI：10.1016/j.dnarep.2006.06.006

• low fidelity DNA polymerase
• immunoglobulin gene
• somatic hypermutation
• class switch recombination

Multiple DNA polymerases participate in somatic hypermutation of immunoglobulin (Ig) genes. Mutations at A/T are largely dependent on DNA polymerase eta (POLH) whereas mutations at C/G appear to be generated by several DNA polymerases. We have previously shown that mice expressing a catalytically inactive POLQ (Polq-inactive) have a reduction in C/G mutations. Here we have generated mice that completely lack Polq expression (Polq-null). Polq-null mice have no obvious abnormality in B or T cell differentiation, and their splenic B cells responded normally to various activation signals and underwent normal Ig gene class switching. The mutant mice mounted relatively normal immune responses against a T-dependent antigen although there was a slight decrease in antigen specific antibodies. Polq-null mice exhibited a mild reduction in the overall mutation frequency, however, in contrast to Polq-inactive mice where the reduction mostly affected mutations at C/G, Polq-null mice showed a reduction of both C/G and A/T mutations and there was a significant increase of G to C transversions. These results confirm a role for POLQ in somatic hypermutation and suggest that in the complete absence of POLQ other polymerases may functionally substitute, resulting in a mutation pattern different from that found in Polq-inactive mice.

• 出版日期2006-11-8