We have identified a unique signature for DNA polymerase zeta which is to generate tandem mutations during somatic hypermutation. Using mice deficient for various polymerases, we observed that polymerase eta is a dominant protein, and the effect of polymerase zeta was more pronounced in the absence of polymerase eta. Furthermore, data suggest that polymerase zeta functions in the MSH2-MSH6 pathway. An advantage to using polymerase zeta to introduce tandem mutations would be to efficiently change amino acids in variable genes to generate higher affinity antibodies. Similarly, we are determining if polymerase iota interacts with the replication fork to compete with polymerase zeta. A study of how proliferating cell nuclear antigen clamp unloaders interfere with cell division and class switch recombination and hypermutation is underway. We are also measuring single-strand breaks in variable genes to see how polymerases gain access to synthesize.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000732-18
Application #
8736602
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2013
Total Cost
$837,455
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Gearhart, Patricia J; Lindahl, Tomas; Neuberger, Michael S (2009) Preface. Philos Trans R Soc Lond B Biol Sci 364:561-2
Saribasak, Huseyin; Rajagopal, Deepa; Maul, Robert W et al. (2009) Hijacked DNA repair proteins and unchained DNA polymerases. Philos Trans R Soc Lond B Biol Sci 364:605-11