Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatic hypermutation (SHM) occurs in the variable region of immunoglobulin genes in germinal center B cells where it plays an important role in affinity maturation of the T cell-dependent immune response. Although the precise mechanism of SHM is still unknown, it has been suggested that error-prone DNA polymerases (Pol) are involved in SHM. Poliota is a member of the error-prone Y-family of DNA polymerases which exhibit translesion synthesis activity in vitro and are highly mutagenic when replicating on non-damaged DNA templates. In BL2 cell line stimulated to induce SHM, the induction is Poliota-dependent. However, in 129-derived strains of mice deficient in Poliota, SHM is normal. One possible explanation for this discrepancy is that a Poliota deficiency in mice might be compensated for by another error-prone DNA polymerase, such as Polkappa, which also belongs to the Y-family of DNA polymerases. Although SHM in Polkappa-deficient mice is normal, their deficiency might be compensated for by Poliota. In this study, we generated Polkappa-Poliota double-deficient mice and examined them for SHM. We found that the double-deficient mice had the normal SHM frequency and profile, rendering them indistinguishable from Polkappa-deficient mice and thus conclude that Poliota and Polkappa are dispensable for SHM in mice.
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PMID:Normal immunoglobulin gene somatic hypermutation in Pol kappa-Pol iota double-deficient mice. 1586 Feb 26

Somatic hypermutation (SHM) is a fundamental process in immunoglobulin gene maturation that results in increased affinity of antibodies toward antigens. In one hypothesis explaining SHM in human B cells, the process is initiated by enzymatic deamination of cytosine to uracil in the immunoglobulin gene V-region and this in turn triggers mutation-prone forms of uracil-DNA base excision repair (BER). Yet, an uncertainty with this model is that BER of uracil-DNA in mammalian cells is generally error-free, wherein DNA polymerase beta (pol beta) conducts gap-filling synthesis by insertion of bases according to Watson-Crick rules. To evaluate this inconsistency, we examined pol beta expression in various SHM proficient human BL2 cell line subclones. We report that expression of pol beta in SHM proficient cell lines was strongly down-regulated. In contrast, in other BL2 subclones, we found that SHM was deficient and that pol beta expression was much higher than in the SHM proficient subclones. We also found that overexpression of recombinant human pol beta in a SHM proficient subclone abrogated its capacity for SHM. These results suggest that down-regulation of the normal BER gap-filling DNA polymerase, pol beta, accompanies induced SHM in BL2 cells. This is consistent with the hypothesis that normal error-free BER must be silenced to make way for an error-prone BER process that may be required during somatic hypermutation.
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PMID:Down-regulation of DNA polymerase beta accompanies somatic hypermutation in human BL2 cell lines. 1712 6