Overexpression of in the saline-treated FA ?mice than in the FA+ mice, the glycosylase caused an imbalance in BER and pro- supporting the idea that folate deiency was protective duced more AP sites and gapped DNA as intermediates against CC-5013 pontaneous?mutations in Aag null animals. (4) in the formation of chromosomal aberrations  . Sim- As in wild-type mice, MMS treatment of Aag null mice ilarly, myeloid progenitor bone marrow cells from Aag caused an increase in mutant frequency compared to null mice were more resistant to the cytotoxic effects saline-treated animals. (5) MMS caused a higher mutant of alkylating agents than wild-type cells  .
These frequency in Aag null mice than in wild-type mice fed observations supported the notion that initiation of base FA+ diets, but the synergistic effect of a FA ?diet was CC-5013 Lenalidomide excision repair is more lethal to some cell types than diminished (3.6-fold versus 9.8-fold). leaving damaged bases unrepaired  . The cell has two defense mechanisms to protect The results reported here conm our prior studies against uracil incorporation into DNA; one is the enzyme showing a synergistic effect of folate deiency and dUTPase that hydrolyses dUTP to dUMP  . The alkylating agents in causing genetic damage, and sup- other mechanism is base excision repair (BER). The port our hypothesis that this effect is mediated through 4 ? 16 R.F. Branda et al. / Mutation Research 615 (2007)2?7 DNA repair. Our dings also support the dings of  Y.-I. Kim, I.P. Pogribny, A.G.
Basnakian, J.W. Miller, J. Sel- other laboratories that AAG plays an important role in hub, S.J. James, J.B. Mason, Folate deiency in rats induces attenuating the mutagenic effects of N- alkylpurines in vivo . However, splenocytes from Aag null mice were more resistant to the cytotoxic effects of alkylating agents than wild-type cells. FA ?conferred less protec- DNA strand breaks and hypomethylation within the p53 tumor suppressor gene, Am. J. Clin. Nutr. 65 (1997) 46?2.  S.J. Duthie, A. Hawdon, DNA instability CC-5013 Revlimid (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro , FASEB J.2 (1998) tion against cytotoxicity and a proportionately greater 1491?497. rise in mutant frequency after alkylator treatment in Aag null mice. Thus, FA ?may facilitate the loss (death?) of genetically damaged AAG null cells by further restrict-  R.B. Everson, C.M. Wehr, G.L. Erexson, J.T. MacGregor, Asso- ciation of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes, J. Natl.
Cancer Inst. 80 (1988) ing the ability of these cells to repair DNA. A FA+ 525?29. diet appears to protect against the cytotoxicity of alky-  C.W. Heath, Cytogenetic observations in Vitamin B12 and folate lating agents in repair-deient animals but increases the frequency of DNA mutation after alkylator treat- ment. We conclude that FA ?increases the frequency of deiency, Blood 27 (1966) 800?15.  B.L. Libbus, L.S. Borman, C.H. Ventrone, R.F. Branda, Nutritional folate-deiency in Chinese hamster ovary cells: chro- mosomal abnormalities associated with perturbations in nucleic DNA seas mutations after alkylating agent treatment in DNA acid precursor, Cancer Genet. Cytogenet. 46 (1990) 231?42. repair-competent but not repair-deient animals. Thus,  S.J. Duthie, P. McMillan, Uracil misincorporation in human DNA depending upon the cellular DNA repair status, FA ? may either not affect or increase cyototoxicity and either increase or decrease the frequency of DNA mutations. detected using single cell gel electrophoresis, Carcinogenesis8 (1997)709?714.  S.N. Wickramasinghe, S. Fida, Misincorporation of uracil into the DNA of folate- and B12-deient HL60 cells, Eur. J. Haematol. These results may explain, at least in part, why folate 50 (1993)27?32. deiency has had enhancing or inhibiting effects on car-  B.C.