title: Susceptibility to intestinal tumorigenesis in folate-deficient mice may be influenced by variation in one-carbon metabolism and DNA repair.
abstract: Low dietary folate is associated with increased risk of colorectal cancer. In earlier work, we showed that folate deficiency induced intestinal tumors in BALB/c but not C57Bl/6 mice through increased dUTP incorporation into DNA with consequent DNA damage. To determine whether strain differences between one-carbon metabolism and DNA repair pathways could contribute to increased tumorigenesis in BALB/c mice, we measured amino acids and folate in the normal intestinal tissue of both strains fed a control diet or a folate-deficient diet. We also determined the expression of critical folate-metabolizing enzymes and several DNA repair enzymes. BALB/c mice had lower intestinal serine (major cellular one-carbon donor), methionine and total folate than C57Bl/6 mice under both dietary conditions. BALB/c mice had higher messenger RNA and protein levels of three folate-interconverting enzymes: trifunctional methyleneTHF (5,10-methylenetetrahydrofolate) dehydrogenase-methenylTHF cyclohydrolase-formylTHF (10-formyltetrahydrofolate) synthetase 1, bifunctional methyleneTHF dehydrogenase-methenylTHF cyclohydrolase and methylenetetrahydrofolate reductase. This pattern of expression could limit the availability of methyleneTHF for conversion of dUMP to dTMP. BALB/c mice also had higher levels of uracil DNA glycosylase 2 protein without an increase in the rate-limiting DNA polymerase β enzyme, compared with C57Bl/6 mice. We conclude that BALB/c mice may be more prone to DNA damage through decreased amounts of one-carbon donors and the diversion of methyleneTHF away from the conversion of dUMP to dTMP. In addition, incomplete excision repair of uracil in DNA could lead to accumulation of toxic repair intermediates and promotion of tumorigenesis in this tumor-susceptible strain.
authors.affiliation: Department of Human Genetics, McGill University-Montreal Children's Hospital, Montreal, Quebec, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Knock
authors.forename: Liyuan
authors.initials: L
authors.lastname: Deng
authors.forename: Natalia
authors.initials: N
authors.lastname: Krupenko
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Mohan
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.forename: C Lee
authors.initials: CL
authors.lastname: Elmore
authors.forename: Warren
authors.initials: W
authors.lastname: Kruger
authors.forename: Marc
authors.initials: M
authors.lastname: Tini
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000619:Aminohydrolases / Q000378:metabolism*; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004032:Diet; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000150:complications* / Q000235:genetics; D005574:Formate-Tetrahydrofolate Ligase / Q000378:metabolism*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000378:metabolism*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D012333:RNA, Messenger; D013763:Tetrahydrofolates; C055342:methylene tetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase; C013123:5,10-methylenetetrahydrofolic acid; D012694:Serine; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D019951:DNA Polymerase beta; D051981:Uracil-DNA Glycosidase; D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase