Journal
EMBO REPORTS
Volume 6, Issue 12, Pages 1143-1148Publisher
WILEY
DOI: 10.1038/sj.embor.7400582
Keywords
AID; bypass; DNA polymerase; POLQ; somatic hypermutation; translesion
Categories
Funding
- Intramural NIH HHS Funding Source: Medline
- NCI NIH HHS [CA101980, R01 CA101980, R01 CA098675, CA098675] Funding Source: Medline
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Somatic hypermutation of immunoglobulin variable genes, which increases antibody diversity, is initiated by the activation-induced cytosine deaminase (AID) protein. The current DNA-deamination model posits that AID deaminates cytosine to uracil in DNA, and that mutations are generated by DNA polymerases during replication or repair of the uracil residue. Mutations could arise as follows: by DNA replicating past the uracil; by removing the uracil with a uracil glycosylase and replicating past the resulting abasic site with a low-fidelity polymerase; or by repairing the uracil and synthesizing a DNA-repair patch downstream using a low-fidelity polymerase. In this review, we summarize the biochemical properties of specialized DNA polymerases in mammalian cells and discuss their participation in the mechanisms of hypermutation. Many recent studies have examined mice deficient in the genes that encode various DNA polymerases, and have shown that DNA polymerase H ( POLH) contributes to hypermutation, whereas POLI, POLK and several other enzymes do not have major roles. The low-fidelity enzyme POLQ has been proposed as another candidate polymerase because it can efficiently bypass abasic sites and recent evidence indicates that it might participate in hypermutation.
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